JPS6121559B2 - - Google Patents
Info
- Publication number
- JPS6121559B2 JPS6121559B2 JP55130645A JP13064580A JPS6121559B2 JP S6121559 B2 JPS6121559 B2 JP S6121559B2 JP 55130645 A JP55130645 A JP 55130645A JP 13064580 A JP13064580 A JP 13064580A JP S6121559 B2 JPS6121559 B2 JP S6121559B2
- Authority
- JP
- Japan
- Prior art keywords
- place
- formula
- acid
- compound
- reaction
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- 150000001875 compounds Chemical class 0.000 claims description 73
- 239000002253 acid Substances 0.000 claims description 16
- 150000003839 salts Chemical class 0.000 claims description 10
- GDGDDTIYKPCVEG-NIQDUIQNSA-N (7S,9S)-9-acetyl-7-[(2R,4S,5S,6S)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-6,9-dihydroxy-8,10-dihydro-7H-tetracene-5,12-dione Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C=C2C[C@@](O)(C(C)=O)C1 GDGDDTIYKPCVEG-NIQDUIQNSA-N 0.000 claims description 6
- 229940045799 anthracyclines and related substance Drugs 0.000 claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 125000003712 glycosamine group Chemical group 0.000 claims description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 57
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 51
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 48
- 238000006243 chemical reaction Methods 0.000 description 45
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 34
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 27
- 239000000243 solution Substances 0.000 description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- 239000000284 extract Substances 0.000 description 21
- 238000000034 method Methods 0.000 description 21
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 16
- 229910052938 sodium sulfate Inorganic materials 0.000 description 16
- 235000011152 sodium sulphate Nutrition 0.000 description 16
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 13
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 12
- 239000000203 mixture Substances 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 9
- 238000000354 decomposition reaction Methods 0.000 description 9
- 238000006460 hydrolysis reaction Methods 0.000 description 9
- 239000000741 silica gel Substances 0.000 description 9
- 229910002027 silica gel Inorganic materials 0.000 description 9
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- 230000007062 hydrolysis Effects 0.000 description 8
- -1 n- butyryl Chemical group 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 7
- 230000000259 anti-tumor effect Effects 0.000 description 7
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 7
- 229910052794 bromium Inorganic materials 0.000 description 7
- 210000004027 cell Anatomy 0.000 description 7
- 238000004587 chromatography analysis Methods 0.000 description 7
- 238000011282 treatment Methods 0.000 description 7
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 6
- 206010028980 Neoplasm Diseases 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 125000004423 acyloxy group Chemical group 0.000 description 6
- 238000000434 field desorption mass spectrometry Methods 0.000 description 6
- 230000026030 halogenation Effects 0.000 description 6
- 238000005658 halogenation reaction Methods 0.000 description 6
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 6
- 235000017557 sodium bicarbonate Nutrition 0.000 description 6
- 229940009456 adriamycin Drugs 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 125000006239 protecting group Chemical group 0.000 description 5
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2,2'-azo-bis-isobutyronitrile Substances N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 4
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 4
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 4
- WEAHRLBPCANXCN-UHFFFAOYSA-N Daunomycin Natural products CCC1(O)CC(OC2CC(N)C(O)C(C)O2)c3cc4C(=O)c5c(OC)cccc5C(=O)c4c(O)c3C1 WEAHRLBPCANXCN-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 4
- 230000003197 catalytic effect Effects 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 238000010511 deprotection reaction Methods 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 229930182470 glycoside Natural products 0.000 description 4
- 150000002338 glycosides Chemical class 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 4
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 3
- OZAIFHULBGXAKX-VAWYXSNFSA-N AIBN Substances N#CC(C)(C)\N=N\C(C)(C)C#N OZAIFHULBGXAKX-VAWYXSNFSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 238000005727 Friedel-Crafts reaction Methods 0.000 description 3
- 208000007093 Leukemia L1210 Diseases 0.000 description 3
- 241000699666 Mus <mouse, genus> Species 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- UGJBHEZMOKVTIM-UHFFFAOYSA-N N-formylglycine Chemical compound OC(=O)CNC=O UGJBHEZMOKVTIM-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- LGRFSURHDFAFJT-UHFFFAOYSA-N Phthalic anhydride Natural products C1=CC=C2C(=O)OC(=O)C2=C1 LGRFSURHDFAFJT-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 3
- 239000003377 acid catalyst Substances 0.000 description 3
- 230000000844 anti-bacterial effect Effects 0.000 description 3
- 230000001093 anti-cancer Effects 0.000 description 3
- 125000004429 atom Chemical group 0.000 description 3
- JHIWVOJDXOSYLW-UHFFFAOYSA-N butyl 2,2-difluorocyclopropane-1-carboxylate Chemical compound CCCCOC(=O)C1CC1(F)F JHIWVOJDXOSYLW-UHFFFAOYSA-N 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 210000004748 cultured cell Anatomy 0.000 description 3
- 125000005843 halogen group Chemical group 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 208000032839 leukemia Diseases 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 150000007522 mineralic acids Chemical class 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- NAWXUBYGYWOOIX-SFHVURJKSA-N (2s)-2-[[4-[2-(2,4-diaminoquinazolin-6-yl)ethyl]benzoyl]amino]-4-methylidenepentanedioic acid Chemical compound C1=CC2=NC(N)=NC(N)=C2C=C1CCC1=CC=C(C(=O)N[C@@H](CC(=C)C(O)=O)C(O)=O)C=C1 NAWXUBYGYWOOIX-SFHVURJKSA-N 0.000 description 2
- GHOKWGTUZJEAQD-ZETCQYMHSA-N (D)-(+)-Pantothenic acid Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-ZETCQYMHSA-N 0.000 description 2
- WGTZMBPREOVAOL-UHFFFAOYSA-N 1-(2-hydroxy-5-methoxy-3,4-dihydro-1h-naphthalen-2-yl)ethanone Chemical compound C1C(O)(C(C)=O)CCC2=C1C=CC=C2OC WGTZMBPREOVAOL-UHFFFAOYSA-N 0.000 description 2
- TWCMVXMQHSVIOJ-UHFFFAOYSA-N Aglycone of yadanzioside D Natural products COC(=O)C12OCC34C(CC5C(=CC(O)C(O)C5(C)C3C(O)C1O)C)OC(=O)C(OC(=O)C)C24 TWCMVXMQHSVIOJ-UHFFFAOYSA-N 0.000 description 2
- PLMKQQMDOMTZGG-UHFFFAOYSA-N Astrantiagenin E-methylester Natural products CC12CCC(O)C(C)(CO)C1CCC1(C)C2CC=C2C3CC(C)(C)CCC3(C(=O)OC)CCC21C PLMKQQMDOMTZGG-UHFFFAOYSA-N 0.000 description 2
- 241000192125 Firmicutes Species 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000012980 RPMI-1640 medium Substances 0.000 description 2
- 229920005654 Sephadex Polymers 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- DRTQHJPVMGBUCF-XVFCMESISA-N Uridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-XVFCMESISA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 210000001367 artery Anatomy 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 244000309466 calf Species 0.000 description 2
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- 239000001569 carbon dioxide Substances 0.000 description 2
- 229910002092 carbon dioxide Inorganic materials 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- WPJRFCZKZXBUNI-HCWXCVPCSA-N daunosamine Chemical compound C[C@H](O)[C@@H](O)[C@@H](N)CC=O WPJRFCZKZXBUNI-HCWXCVPCSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000006345 epimerization reaction Methods 0.000 description 2
- 238000000855 fermentation Methods 0.000 description 2
- 230000004151 fermentation Effects 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 238000006206 glycosylation reaction Methods 0.000 description 2
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 2
- PFOARMALXZGCHY-UHFFFAOYSA-N homoegonol Natural products C1=C(OC)C(OC)=CC=C1C1=CC2=CC(CCCO)=CC(OC)=C2O1 PFOARMALXZGCHY-UHFFFAOYSA-N 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 229910000474 mercury oxide Inorganic materials 0.000 description 2
- UKWHYYKOEPRTIC-UHFFFAOYSA-N mercury(ii) oxide Chemical compound [Hg]=O UKWHYYKOEPRTIC-UHFFFAOYSA-N 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 235000011056 potassium acetate Nutrition 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
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- CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Chemical class C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 2
- 210000003462 vein Anatomy 0.000 description 2
- JSLISSGEILAIOU-UHFFFAOYSA-N (4-chloro-2-iodophenyl)hydrazine Chemical compound NNC1=CC=C(Cl)C=C1I JSLISSGEILAIOU-UHFFFAOYSA-N 0.000 description 1
- JBVCUZWDGRKRKU-CYMFRXPCSA-N (7s,9s)-7-[(2r,4s,5s,6s)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-6,9-dihydroxy-9-(2-hydroxyacetyl)-4-methoxy-8,10-dihydro-7h-tetracene-5,12-dione Chemical compound O([C@H]1C[C@@](O)(CC=2C=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 JBVCUZWDGRKRKU-CYMFRXPCSA-N 0.000 description 1
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- UIOXNNAWANDJCZ-UHFFFAOYSA-N 1,1-dimethoxypropane Chemical compound CCC(OC)OC UIOXNNAWANDJCZ-UHFFFAOYSA-N 0.000 description 1
- IQFYYKKMVGJFEH-OYDXRQHMSA-N 1-[(2r,4s,5s)-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-5-methylpyrimidine-2,4-dione Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H]([14CH2]O)[C@@H](O)C1 IQFYYKKMVGJFEH-OYDXRQHMSA-N 0.000 description 1
- LDMOEFOXLIZJOW-UHFFFAOYSA-N 1-dodecanesulfonic acid Chemical compound CCCCCCCCCCCCS(O)(=O)=O LDMOEFOXLIZJOW-UHFFFAOYSA-N 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- MDAIAXRTLTVEOU-UHFFFAOYSA-N 5-methoxy-3,4-dihydro-1h-naphthalen-2-one Chemical compound C1C(=O)CCC2=C1C=CC=C2OC MDAIAXRTLTVEOU-UHFFFAOYSA-N 0.000 description 1
- BRCPWISABURVIH-UHFFFAOYSA-N 5-methoxy-3,4-dihydro-2h-naphthalen-1-one Chemical compound O=C1CCCC2=C1C=CC=C2OC BRCPWISABURVIH-UHFFFAOYSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- PITHJRRCEANNKJ-UHFFFAOYSA-N Aclacinomycin A Natural products C12=C(O)C=3C(=O)C4=CC=CC=C4C(=O)C=3C=C2C(C(=O)OC)C(CC)(O)CC1OC(OC1C)CC(N(C)C)C1OC(OC1C)CC(O)C1OC1CCC(=O)C(C)O1 PITHJRRCEANNKJ-UHFFFAOYSA-N 0.000 description 1
- SMNNBONTPYNICF-UHFFFAOYSA-N Aclacinomycin B Natural products CCC1(O)CC(OC2CC(C(OC3CC(O)C(OC4CCC(=O)CO4)C(C)O3)C(C)O2)N(C)C)c5c(O)c6C(=O)c7ccccc7C(=O)c6cc5C1C(=O)OC SMNNBONTPYNICF-UHFFFAOYSA-N 0.000 description 1
- 241000186361 Actinobacteria <class> Species 0.000 description 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- 101100005765 Arabidopsis thaliana CDF1 gene Proteins 0.000 description 1
- 101100007579 Arabidopsis thaliana CPP1 gene Proteins 0.000 description 1
- 206010003445 Ascites Diseases 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- 238000006418 Brown reaction Methods 0.000 description 1
- GHOKWGTUZJEAQD-UHFFFAOYSA-N Chick antidermatitis factor Natural products OCC(C)(C)C(O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 230000006820 DNA synthesis Effects 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 238000003747 Grignard reaction Methods 0.000 description 1
- 239000007818 Grignard reagent Substances 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 1
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 235000021314 Palmitic acid Nutrition 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 230000006819 RNA synthesis Effects 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- PQLVXDKIJBQVDF-UHFFFAOYSA-N acetic acid;hydrate Chemical compound O.CC(O)=O PQLVXDKIJBQVDF-UHFFFAOYSA-N 0.000 description 1
- USZYSDMBJDPRIF-SVEJIMAYSA-N aclacinomycin A Chemical compound O([C@H]1[C@@H](O)C[C@@H](O[C@H]1C)O[C@H]1[C@H](C[C@@H](O[C@H]1C)O[C@H]1C[C@]([C@@H](C2=CC=3C(=O)C4=CC=CC(O)=C4C(=O)C=3C(O)=C21)C(=O)OC)(O)CC)N(C)C)[C@H]1CCC(=O)[C@H](C)O1 USZYSDMBJDPRIF-SVEJIMAYSA-N 0.000 description 1
- 229960004176 aclarubicin Drugs 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- QBYJBZPUGVGKQQ-SJJAEHHWSA-N aldrin Chemical compound C1[C@H]2C=C[C@@H]1[C@H]1[C@@](C3(Cl)Cl)(Cl)C(Cl)=C(Cl)[C@@]3(Cl)[C@H]12 QBYJBZPUGVGKQQ-SJJAEHHWSA-N 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical group 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical group 0.000 description 1
- 239000012670 alkaline solution Substances 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O ammonium group Chemical group [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 229940039409 ammonium valerate Drugs 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000003817 anthracycline antibiotic agent Substances 0.000 description 1
- 230000009876 antimalignant effect Effects 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 125000005098 aryl alkoxy carbonyl group Chemical group 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- XJMWHXZUIGHOBA-UHFFFAOYSA-N azane;propanoic acid Chemical compound N.CCC(O)=O XJMWHXZUIGHOBA-UHFFFAOYSA-N 0.000 description 1
- TWJVNKMWXNTSAP-UHFFFAOYSA-N azanium;hydroxide;hydrochloride Chemical class [NH4+].O.[Cl-] TWJVNKMWXNTSAP-UHFFFAOYSA-N 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- OHDBYQSGLSTIHF-UHFFFAOYSA-N benzenesulfonic acid;methanesulfonic acid Chemical compound CS(O)(=O)=O.OS(=O)(=O)C1=CC=CC=C1 OHDBYQSGLSTIHF-UHFFFAOYSA-N 0.000 description 1
- CSKNSYBAZOQPLR-UHFFFAOYSA-N benzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- DRTQHJPVMGBUCF-PSQAKQOGSA-N beta-L-uridine Natural products O[C@H]1[C@@H](O)[C@H](CO)O[C@@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-PSQAKQOGSA-N 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 238000007664 blowing Methods 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- QDHFHIQKOVNCNC-UHFFFAOYSA-N butane-1-sulfonic acid Chemical compound CCCCS(O)(=O)=O QDHFHIQKOVNCNC-UHFFFAOYSA-N 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 125000001589 carboacyl group Chemical group 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 150000001734 carboxylic acid salts Chemical class 0.000 description 1
- 229920001429 chelating resin Polymers 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 208000037516 chromosome inversion disease Diseases 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000003795 desorption Methods 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- 230000009036 growth inhibition Effects 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 150000003949 imides Chemical class 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000005907 ketalization reaction Methods 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- FRIJBUGBVQZNTB-UHFFFAOYSA-M magnesium;ethane;bromide Chemical compound [Mg+2].[Br-].[CH2-]C FRIJBUGBVQZNTB-UHFFFAOYSA-M 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- XELZGAJCZANUQH-UHFFFAOYSA-N methyl 1-acetylthieno[3,2-c]pyrazole-5-carboxylate Chemical compound CC(=O)N1N=CC2=C1C=C(C(=O)OC)S2 XELZGAJCZANUQH-UHFFFAOYSA-N 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- 238000001668 nucleic acid synthesis Methods 0.000 description 1
- 239000006916 nutrient agar Substances 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 235000021313 oleic acid Nutrition 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 239000011713 pantothenic acid Substances 0.000 description 1
- 229940055726 pantothenic acid Drugs 0.000 description 1
- 235000019161 pantothenic acid Nutrition 0.000 description 1
- 210000003200 peritoneal cavity Anatomy 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 229960004109 potassium acetate Drugs 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- BWILYWWHXDGKQA-UHFFFAOYSA-M potassium propanoate Chemical compound [K+].CCC([O-])=O BWILYWWHXDGKQA-UHFFFAOYSA-M 0.000 description 1
- 239000004331 potassium propionate Substances 0.000 description 1
- 235000010332 potassium propionate Nutrition 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- RQHZAASWYUEYCJ-JVWHUAOPSA-N siwenmycin Chemical compound O=C1C2=C(O)C=CC=C2C(=O)C2=C1C(O)=C1[C@@H](O[C@@H]3O[C@@H](C)[C@@H](O[C@@H]4O[C@@H](C)[C@H]5O[C@@H]6O[C@H](C)C(=O)C[C@@H]6O[C@H]5C4)[C@H](C3)N(C)C)C[C@@](CC)(O)[C@H](C(=O)OC)C1=C2 RQHZAASWYUEYCJ-JVWHUAOPSA-N 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 229960004249 sodium acetate Drugs 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- JXKPEJDQGNYQSM-UHFFFAOYSA-M sodium propionate Chemical compound [Na+].CCC([O-])=O JXKPEJDQGNYQSM-UHFFFAOYSA-M 0.000 description 1
- 239000004324 sodium propionate Substances 0.000 description 1
- 235000010334 sodium propionate Nutrition 0.000 description 1
- 229960003212 sodium propionate Drugs 0.000 description 1
- LHYPLJGBYPAQAK-UHFFFAOYSA-M sodium;pentanoate Chemical compound [Na+].CCCCC([O-])=O LHYPLJGBYPAQAK-UHFFFAOYSA-M 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- DRTQHJPVMGBUCF-UHFFFAOYSA-N uracil arabinoside Natural products OC1C(O)C(CO)OC1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-UHFFFAOYSA-N 0.000 description 1
- 229940045145 uridine Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/32—Oxygen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C43/00—Ethers; Compounds having groups, groups or groups
- C07C43/02—Ethers
- C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
- C07C43/215—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring having unsaturation outside the six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/26—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by hydration of carbon-to-carbon triple bonds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/16—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D309/28—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D309/30—Oxygen atoms, e.g. delta-lactones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
- C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
- C07H13/08—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals directly attached to carbocyclic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/20—Carbocyclic rings
- C07H15/24—Condensed ring systems having three or more rings
- C07H15/252—Naphthacene radicals, e.g. daunomycins, adriamycins
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Description
本発明は新規なアントラサイクリン誘導体に関
し、さらに詳しくは下記一般式
式中、R1は水素原子又は水酸基を表わす、
で示されるアンスラサイクリン誘導体又はその酸
付加塩に関する。
アントラサイクリン系抗生物質としては、従来
から放線菌の培養液から得られるダウノマイシン
（米国特許第3616242号明細書参照）及びアドリア
マイシン（米国特許第3590028号明細書参照）が
知られており、これら化合物は、実験腫瘍に対し
て広い抗癌スペクトルを有し、癌化学療法剤とし
て臨床的にも広く利用されている。しかし、ダウ
ノマイシン及びアドリアマイシンはかなり強力な
抗癌作用を示すが、決して満足できるものではな
く、より強力な抗癌作用を有する化合物を見い出
すべく、発酵法、半合成法、全合成法、微生物変
換法等各種の手段により種々の類縁化合物を創製
する試みが行われており、既にいくつか提案され
ている〔例えば、F.Arcamone，Topico in
Antibiotic ChemistryVol2，第102〜279頁，
ELLIS HORWOOD LIMITED発行；特公昭51−
34915号公報（アクラシノマイシンＡ及びＢ）；
特開昭54―30146号公報（４―Ｏ―テトラヒドロ
ピラニルアドリアマイシン）等参照〕。
本発明もまた、ダウノマイシン及びアドリアマ
イシンのより高活性の類縁化合物を提供すること
を目的として完成されたものであり、本発明によ
り提供される前記式（）の化合物、殊に下記式
式中、R11は水素原子又は水酸基を表わす、
で示される化合物、すなわち、４―デメトキシ―
11―デオキシダウノマイシン（R11＝Ｈ）もしく
は４―デメトキシ―11―デオキシアドリアマイシ
ン（R11＝OH）、又はこれらの酸付加塩は、後述
する如く優れた抗腫瘍活性を有しており、抗癌剤
としての用途が考えられる。
なお下記式
式中、R1は前記の意味を有する、
で示されるアグリコン、すなわち４―デメトキシ
―11―デオキシダウノマイシノン（R1＝Ｈ）又
は４―デメトキシ―11―デオキシアドリアマイシ
ノンもしくはその14―低級アルカノイル誘導体
（R1＝OH）又は低級アルカノイルオキシ基）
は、上記式（ｌ―ａ―１）の化合物等の如き医薬
等として有用なアントラサイクリン系化合物を合
成するための重要な中間体として有用である。
本明細書において「低級」なる語は、この語が
付された基又は化合物の炭素原子数が６個以下、
好ましくは４個以下であることを意味する。
しかして、前記式(A)おいて、R1によつて表わ
される「低級アルカノイルオキシ基」は、アルキ
ル部分が直鎖状又は分岐鎖で且つ１〜５個、好ま
しくは１〜３個の炭素原子を有するアルカン酸残
基であり、例えばアセチル、プロピオニル、ｎ―
ブチリール、イソブチリール、ｎ―ペンチール、
イソペンチール等が包含される。かかる低級アル
カノイルオキシ基としては特にアセチル基が好適
である。
また、前記式（ｌ―ａ―１）の化合物の酸付加
塩としては中でも製薬学的に許容しうる酸との塩
が好ましく、かかる酸の例としては、塩化水素
酸、臭化水素酸、硫酸、リン酸などの無機酸、或
いは酢酸、プロピオン酸、マレイン酸、オレイン
酸、パルミチン酸、クエン酸、コハク酸、酒石
酸、フマール酸、グルタミン酸、パントテン酸、
ラウリルスルホン酸、メタンスルホン酸、ナフタ
レンスルホン酸などの有機酸が挙げられる。
本発明により提供される前記式()の化合物
は、例えば、下記反応式に示す合成経路により全
合成することができる。
上記反応式において、R1は前記の意味を有
し、R12は水素原子又は低級アルカノイルオキシ
基を表わし；R3は低級アルキル基を表わし；X1
及びX2はそれぞれハロゲン原子、特に臭気原子
を表わし；Ｚはケタール残基を表わし、Ｍはアル
カリ金属原子、アルカリ土類金属原子、又はアン
モニウム基を表わし、R′及びR″はそれぞれ加水
分解により容易に除去しうるアミノ保護基又はヒ
ドロキシル保護基を表わす。
上記反応式に示す各段の単位反応はそれ自体既
知のものであり、既知の方法で実施することがで
きるが、各段の反応について簡単に説明すれば次
のとおりである。
(1)→(2)
本段階では、式(1)の５―メトキシテトラロンを
式（CH≡Ｃ）MgX3のグリニヤール試薬（ここで
X3はハロゲン原子、殊に臭素原子を表わす）と
反応させることにより、式(2)のテトラリン誘導体
に変えることができる。本反応はそれ自体公知の
グリニヤール反応を利用して行なうことができ
る。
(2)→(3)
本段階では、式(2)のテトラリン誘導体を加水分
解することにより２―アセチル―２―ヒドロキシ
―５―メトキシ―１，２，３，４―テトラヒドロ
ナフタレンに変える。この加水分解は例えば、式
(2)の化合物を酸化水銀の存在下に硫酸で処理する
ことにより行なうことができる。
かくして生成する式(3)の化合物は通常の分離精
製法、例えばクロマトグラフイーにより反応混合
物から単離することができる。
(3)→(4)
本段階では、上記の如くして生成せしめられた
式(3)の化合物を無水フタル酸と反応せしめること
により、式(4)の４―デメトキシ―７，11―ジデオ
キシダウノマイシンが製造される。式(3)の化合物
と無水フタル酸との反応はFriedel―Crafts反応
に従つて行なうことができる。例えば、本反応は
ルイス酸の存在下に50〜250℃、特に150〜200℃
の温度において１〜30分間、好ましくは５〜10分
間で終了させることができる。
このFriedel―Crafts反応は溶媒の不在下且つ
比較的高温（約150℃以上）に行なうことが好ま
しく、これによつて以下に述べる如き副反応を効
果的に防ぐことができる。
すなわち、該Friedel―Crafts反応を、通常用
いられる有機溶媒下で実施するか、または比較的
低温（約140℃以下の反応温度）で実施すると、
目的とする式(4)の化合物に加えて、下記式
で示される化合物が副生し、式(4)の化合物の収率
を低下させるが、溶媒の不在下に比較的高温で該
反応を行なえば、かかる副生成物が生ずることな
く、式(4)の化合物を選択的に高収率で得ることが
できることが判明したのである。
(4)→(5)→(6)
本段階の反応はそれ自体公知の方法、例えば米
国特許第3803124号明細書に記載の方法に準じて
行なうことができ、或いは式(4)の化合物のハロゲ
ン化はＮ―ブロモコハク酸イミド又はＮ―クロロ
コハク酸イミドなどのＮ―ハロ酸イミド、殊にＮ
―ブロモコハク酸イミドを用いて行なうことがで
き、これにより式(4)の化合物の14―位のみを選択
的にハロゲン化することができる。このＮ―ハロ
酸イミドによるハロゲン化は通常０〜50℃の温度
において約２〜10時間かけて行なうことができ
る。
式(5)の化合物の式R3COOMの有機カルボン酸
の塩によるアシル化は、通常、不活性溶媒、例え
ばアセトン、メチルイソブチルケトン等のケトン
類または、テトラヒドロフラン、ジオキサン等の
エーテル類の単独またはそれらの混合溶媒中で０
〜80℃の温度において約５〜20時間かけて行なう
ことができる。
ここで使用しうる有機カルボン酸の塩として
は、例えば、酢酸ナトリウム、酢酸カリウム、酢
酸アンモニウム、プロピオン酸ナトリウム、プロ
ピオン酸カリウム、プロピオン酸アンモニウム、
吉草酸ナトリウム、吉草酸アンモニウム等を挙げ
ることができる。
(4)→(8)
本段階の反応は、式(4)の化合物の13―位のカル
ボニ基のケタール化反応であり、それ自体公知の
カルボニル保護試薬（ケタール化剤）を用い、そ
れ自体公知の方法を用いて行なうことができる。
例えば、式HO―Ｚ―OHで示されるケタール化
剤を酸触媒、例えばｐ―トルエンスルホン酸、ベ
ンゼンスルホン酸等の芳香族スルホン酸の存在下
に式(4)の化合物に作用させることにより行なうこ
とができる。
ここでケタール残基Ｚとしては例えば
―CH2CH2―，
The present invention relates to a novel anthracycline derivative, more specifically, it has the following general formula: In the formula, R 1 represents a hydrogen atom or a hydroxyl group, and relates to an anthracycline derivative or an acid addition salt thereof represented by: As anthracycline antibiotics, daunomycin (see US Pat. No. 3,616,242) and adriamycin (see US Pat. No. 3,590,028), which are obtained from the culture solution of actinomycetes, have been known. It has a broad anticancer spectrum against experimental tumors and is widely used clinically as a cancer chemotherapeutic agent. However, although daunomycin and adriamycin exhibit fairly strong anticancer effects, they are by no means satisfactory.In order to find compounds with even stronger anticancer effects, fermentation methods, semisynthetic methods, total synthetic methods, and microbial conversion methods have been used. Attempts have been made to create various analogous compounds by various means, and some proposals have already been made [for example, F.Arcamone, Topico in
Antibiotic Chemistry Vol. 2, pp. 102-279,
Published by ELLIS HORWOOD LIMITED; Tokuko Showa 51-
Publication No. 34915 (Aclacinomycin A and B);
See JP-A-54-30146 (4-O-tetrahydropyranyl adriamycin), etc.]. The present invention has also been completed with the aim of providing more highly active analogues of daunomycin and adriamycin, and the compounds of the formula () provided by the present invention, particularly the following formula: In the formula, R 11 represents a hydrogen atom or a hydroxyl group, i.e., a compound represented by 4-demethoxy-
11-deoxydaunomycin (R 11 =H) or 4-demethoxy-11-deoxyadriamycin (R 11 =OH), or their acid addition salts, have excellent antitumor activity as described below, and are used as anticancer agents. Possible uses are: The following formula In the formula, R 1 has the above-mentioned meaning, an aglycone represented by: 4-demethoxy-11-deoxydaunomycinone (R 1 =H) or 4-demethoxy-11-deoxyadriamycinone or its 14- lower alkanoyl derivative (R 1 =OH) or lower alkanoyloxy group)
is useful as an important intermediate for synthesizing anthracycline compounds useful as medicines, such as the compound of formula (la-1) above. In this specification, the term "lower" refers to a group or compound to which this term is attached having 6 or less carbon atoms;
This means that the number is preferably 4 or less. Therefore, in the above formula (A), the "lower alkanoyloxy group" represented by R 1 has a linear or branched alkyl moiety and 1 to 5 carbon atoms, preferably 1 to 3 carbon atoms. Alkanoic acid residues having atoms, such as acetyl, propionyl, n-
butyryl, isobutyryl, n-pentyl,
Includes isopentyl and the like. An acetyl group is particularly suitable as such lower alkanoyloxy group. Among the acid addition salts of the compound of formula (1-a-1), salts with pharmaceutically acceptable acids are preferred, and examples of such acids include hydrochloric acid, hydrobromic acid, Inorganic acids such as sulfuric acid and phosphoric acid, or acetic acid, propionic acid, maleic acid, oleic acid, palmitic acid, citric acid, succinic acid, tartaric acid, fumaric acid, glutamic acid, pantothenic acid,
Examples include organic acids such as lauryl sulfonic acid, methanesulfonic acid, and naphthalene sulfonic acid. The compound of formula () provided by the present invention can be totally synthesized, for example, by the synthetic route shown in the reaction formula below. In the above reaction formula, R 1 has the above meaning, R 12 represents a hydrogen atom or a lower alkanoyloxy group; R 3 represents a lower alkyl group; X 1
and X 2 each represent a halogen atom, especially an odor atom; Z represents a ketal residue, M represents an alkali metal atom, an alkaline earth metal atom, or an ammonium group; R′ and R″ each represent a halogen atom, in particular an odor atom; Represents an amino-protecting group or a hydroxyl-protecting group that can be easily removed.The unit reactions at each stage shown in the above reaction formula are known per se, and can be carried out by known methods. A brief explanation is as follows: (1)→(2) In this step, 5-methoxytetralone of formula (1) is mixed with a Grignard reagent of formula (CH≡C) MgX 3 (here,
X 3 represents a halogen atom, in particular a bromine atom), to give the tetralin derivative of formula (2). This reaction can be carried out using the Grignard reaction, which is known per se. (2)→(3) In this step, the tetralin derivative of formula (2) is hydrolyzed to convert it into 2-acetyl-2-hydroxy-5-methoxy-1,2,3,4-tetrahydronaphthalene. This hydrolysis can be carried out, for example, by the formula
This can be carried out by treating the compound (2) with sulfuric acid in the presence of mercury oxide. The compound of formula (3) thus produced can be isolated from the reaction mixture by conventional separation and purification methods, such as chromatography. (3)→(4) In this step, the 4-demethoxy-7,11-dideoxy compound of formula (4) is reacted with phthalic anhydride to form the compound of formula (3) produced as described above. Daunomycin is produced. The reaction between the compound of formula (3) and phthalic anhydride can be carried out according to the Friedel-Crafts reaction. For example, this reaction can be carried out at 50-250℃, especially 150-200℃ in the presence of a Lewis acid.
It can be completed in 1 to 30 minutes, preferably 5 to 10 minutes, at a temperature of . This Friedel-Crafts reaction is preferably carried out in the absence of a solvent and at a relatively high temperature (about 150°C or higher), thereby effectively preventing side reactions such as those described below. That is, when the Friedel-Crafts reaction is carried out in a commonly used organic solvent or at a relatively low temperature (reaction temperature of about 140°C or less),
In addition to the target compound of formula (4), the following formula The compound represented by formula (4) is produced as a by-product, reducing the yield of the compound of formula (4). However, if the reaction is carried out at a relatively high temperature in the absence of a solvent, such a by-product is not produced and the yield of the compound of formula (4) is reduced. It was found that the compound () can be selectively obtained in high yield. (4)→(5)→(6) The reaction in this step can be carried out according to a method known per se, for example, the method described in US Pat. No. 3,803,124, or the reaction of the compound of formula (4) Halogenation is an N-haloimide such as N-bromosuccinimide or N-chlorosuccinimide, especially N-
- Bromosuccinimide can be used to selectively halogenate only the 14-position of the compound of formula (4). This halogenation with N-haloacid imide can be carried out usually at a temperature of 0 to 50°C over a period of about 2 to 10 hours. Acylation of the compound of formula (5) with a salt of an organic carboxylic acid of the formula R 3 COOM is usually carried out using an inert solvent, for example, a ketone such as acetone or methyl isobutyl ketone, or an ether such as tetrahydrofuran or dioxane alone or in an inert solvent. 0 in those mixed solvents
It can be carried out at a temperature of -80°C for about 5 to 20 hours. Examples of the organic carboxylic acid salts that can be used here include sodium acetate, potassium acetate, ammonium acetate, sodium propionate, potassium propionate, ammonium propionate,
Examples include sodium valerate and ammonium valerate. (4)→(8) The reaction in this step is a ketalization reaction of the carbonyl group at the 13-position of the compound of formula (4), using a known carbonyl protecting reagent (ketalizing agent). This can be done using a known method.
For example, this is carried out by allowing a ketalizing agent represented by the formula HO-Z-OH to act on the compound of formula (4) in the presence of an acid catalyst, such as an aromatic sulfonic acid such as p-toluenesulfonic acid or benzenesulfonic acid. be able to. Here, the ketal residue Z is, for example, -CH 2 CH 2 -,
【式】【formula】
【式】等が挙げられ、従つて、上記ケタ
ール化剤の具体例には、エチレングリコール、プ
ロピレングリコール、１，１―ジメトキシプロパ
ン、トリエトキシメチン等が包含される。
(6)→(7)及び(8)→(9)
これらの段階は、式(6)又は(8)の化合物の７―位
のハロゲン化工程であり、このハロゲン化はそれ
自体公知のハロゲン化剤、例えば臭素、塩素、Ｎ
―ブロモコハク酸イミド、Ｎ―クロルコハク酸イ
ミド等を用いて行なうことができる。殊にブロム
化することが望ましい。
好適には、フリーラジカル発生剤、例えば２，
２―アゾビスイソブチロニトリル（以下AIBNと
略記する）等の存在下に水性媒体中でブロム溶液
を添加し、一般に０〜60℃、好ましくは室温にお
いて１〜10時間反応せしめることによつて行なう
ことができる。
(7)又は(9)→（Ａ―１）
本段階の反応は加水分解工程である。式(7)又は
(9)の化合物は不安定であるため、上記ハロゲン化
工程を水の存在下で実施する場合には、該ハロゲ
ン化工程中に容易に加水分解反応が起り、対応す
る式（Ａ―１）の化合物が生成することがある
が、該加水分解は一般にアルカリ水溶液を用い常
法で行なうことができる。
かくして式（Ａ―１）の化合物は、一般に、そ
れぞれ（7S，9S）、（7R，9R）、（7R，9S）及び
（7S，9R）の立体配置を有する４種の立体異性体
の混合物として得られる。
式（Ａ―１）の化合物のかかる立体異性体混合
物からのラセミ体（7S，9S；7R，9R）とラセミ
体（7R，9S；7S，9R）との分離は、常法に従
い、例えばクロマトグラフイー法によつて容易に
行なうことができる。
本発明において式（ｌ―ａ―１）の目的化合物
は特に（7S，9S）立体配置を有することが好適
であり、従つて、上記分離されやラセミ体
（7R，9S；7S，9R）はエピ化反応に付すること
により、ラセミ体（7S，9S；7R，9R）に変える
ことができ、これによつてその収量を向上させる
ことができる。このエピ化反応は、例えば、アセ
トン、テトラヒドロフラン、ジオキサン等の水溶
性有機溶媒中、無機酸、例えば、塩酸、過塩素
酸、等の存在下に10℃から使用溶媒の沸点までの
温度範囲内で行なうことができる。
（Ａ―１）→（）
本段階において、式（Ａ―１）の化合物が、ダ
ウノサミンから誘導した下記式
で示されるグリカールと反応せしめられ、式
（）のグリコシドが得られる。
上記式(10)におけるアミノ保護基R′としては、
加水分解により容易に除去しうる保護基、例え
ば、アセチル、プロピオニル、トリフルオロアセ
チル、等の低級アルカノイル基；ベンゾイル、ｐ
―ニトロベンゾイル等の芳香族カルボニル基；ベ
ンジルオキシカルボニル、ｔ―ブトキシカルボニ
ル等のアラルキルオキシカルボニル及びアルキル
オキシカルボニル基等が挙げられ、また、ヒドロ
キシル保護基R″としての加水分解により容易に
除去しうる保護基もまた、ほぼ上記アミノ保護基
R′と同様の基とすることができる。
上記のグリコシル化反応は、それ自体公知の酸
触媒を用いる方法によつて実施でき、通常、無水
の有機溶媒例えば、ベンゼン、トルエン、テトラ
ヒドロフラン、ジオキサン等好ましくは、ベンゼ
ン、トルエン等の芳香族炭化水素中で、酸触媒例
えば、ｐ―トルエンスルホン酸、ベンゼンスルホ
ン酸等の芳香族スルホン酸；メタンスルホン酸、
ブタンスルホン酸等のアルキルスルホン酸の存在
下に行なうことができる。反応温度は通常０〜80
℃、好ましくは20〜40℃が有利である。
なお、上記式(10)のグリカールは、３―アミノ基
及び４―ヒドロキシル基を上記の如き基で保護し
たダウノサミン誘導体を、有機溶媒中又は溶媒を
用いず、塩基例えばピリジン、ジメチルアニリ
ン、モルホリン、トリエチルアミン等の存在下に
スルホニル化剤例えばｐ―トルエンスルホン酸ク
ロライド、ベンゼンスルホン酸クロライド等で処
理することにより製造することができる（特公昭
54−27346号公報参照）。
上記のグリコシル化反応によれば、式（）の
グリコシドは通常、アミノ糖残基が1′α―結合を
有するもの（以下1′α―体という）と1′β―結合
を有するもの（以下1′β―体という）の混合物と
して得られるが、一般に1′α―体が主体をなして
いる。
従つて、式（Ａ―１）の化合物の（7S，9S；
7R，9R）ラセミ体を出発原料として使用する場
合、式（）のグリコシドは、（7S，9S，
1′α）、（7S，9S，1′β）、（7R，9R，1′α）及び
（7R，9R，1′β）の４種の立体異性体の混合物と
なるが、これらの異性体は、例えばシリカゲル等
を用いるクロマトグラフイーにより個々に単離す
ることができる。
なお、この立体異性体の単離は、後述する脱保
護基反応の終了後に行なつてもよい。
（）→（１―ａ）
本段階は式（）の化合物の脱保護基反応工程
であり、この脱保護基反応はそれ自体公知の加水
分解法により行なうことができる。この加水分解
により、式（）の化合物から保護基R′及び
R″を離脱せしめることができ、また、R12が低級
アルカノイルオキシ基である場合には、加水分解
の条件次第で低級アルカノイル基も離脱し、R1
がOHを表わす対応する式（―ａ）の化合物を
生成せしめることもできる。
かくして、前記式（―ａ）で示されるアント
ラサイクリン誘導体が好収率で得られる。なお、
本明細書に示した式のアグリコン部分はいずれも
平面構造的に図示されているが、これら式には、
（7S，9S）（7R，9R）、（7S，9R）及び（7R，
9S）のすべての立体配置を包含する意味で使用
するものである。
さらにまた、上記方法において製造されるR12
が水素原子を表わす式（）の化合物は、前述し
た(4)→(5)→(6)の工程に付することにより、R1が
低級アルカノイルオキシ基を表わす対応する式
（）の化合物に変えることができる。
上記の如くして得られる式（―ａ）の化合物
はそれ自体公知の方法に従い、前述した如き無機
又は有機の酸で処理することにより酸付加塩に変
えることができる。
式（―ａ）の化合物は前述したように優れた
抗腫瘍活性を有しており、中でも、発酵法により
産生するダウノマイシンやアドリアマイシンと同
じ立体配置をもつもの、即ち、（7S，9S）立体配
置をもつものが特に好適であり、また、グリコシ
ドは1′α―結合を有していることが望ましい。
本発明により提供される前記式（―ａ）の化
合物の抗腫瘍活性は以下に述べる実験によつて立
証することができる。
(A) マウス白血病L1210培養細胞に対する増殖、
並びにDNA合成及びRNA合成阻害作用
本発明の化合物はマウス白血病培養細胞
（L1210）の増殖及び核酸合成を顕著に抑制す
る。例えば、20％仔牛血清を含むRPMI1640培地
（ロースウエルパーク研究所1640）へL1210細胞
を５×104ケ／ml接種し、同時に本発明の化合物
を0.1及び0.5μｇ／mlの濃度で添加し、37℃にて
炭酸ガス培養器中で培養し対照区に対する50％増
殖阻害濃度を求めた。更に上記のL1210培養細胞
を10％仔牛血清を含むRPMI1640の培地へ５×105
ケ／mlとなるように懸濁し、37℃にて炭酸ガス培
養器中で１〜２時間培養を行つた後、本発明の化
合物を種々の濃度で添加し、15分後に更に14C―
ウリジン（0.05μCi／ml）及び14C―チミジン
（0.05μCi／ml）を添加し、37℃にて60分間培養
した。反応液へ10％トリクロル酢酸溶液を添加
し、反応を停止すると同時に、酸不溶物を沈殿さ
せ、10〜５％トリクロル酢酸にて更に３回洗浄し
た後ギ酸に溶解し、酸不溶物中の放射活性を測定
し対照区に対する放射能の取込み率から10％、50
％および90％取込み阻害濃度を求めた。結果を第
１表に示す。[Formula] etc. Therefore, specific examples of the above-mentioned ketalizing agent include ethylene glycol, propylene glycol, 1,1-dimethoxypropane, triethoxymethine and the like. (6)→(7) and (8)→(9) These steps are halogenation steps at the 7-position of the compound of formula (6) or (8), and this halogenation is performed using a known halogen. oxidizing agents, such as bromine, chlorine, N
- It can be carried out using bromosuccinimide, N-chlorosuccinimide, etc. In particular, bromination is desirable. Suitably a free radical generator, such as 2,
By adding a bromine solution in an aqueous medium in the presence of 2-azobisisobutyronitrile (hereinafter abbreviated as AIBN), etc., and reacting for 1 to 10 hours generally at 0 to 60°C, preferably at room temperature. can be done. (7) or (9)→(A-1) The reaction at this stage is a hydrolysis step. Formula (7) or
Since the compound (9) is unstable, when the above halogenation step is carried out in the presence of water, a hydrolysis reaction easily occurs during the halogenation step, and the corresponding formula (A-1) However, the hydrolysis can generally be carried out in a conventional manner using an aqueous alkaline solution. Thus, the compound of formula (A-1) is generally a mixture of four stereoisomers having the configurations (7S, 9S), (7R, 9R), (7R, 9S) and (7S, 9R), respectively. obtained as. The racemic form (7S, 9S; 7R, 9R) and the racemic form (7R, 9S; 7S, 9R) of the compound of formula (A-1) from such a stereoisomer mixture can be separated according to a conventional method, for example, by chromatography. This can be easily done using the graphie method. In the present invention, it is particularly preferable that the target compound of formula (1-a-1) has a (7S,9S) configuration. By subjecting it to an epimerization reaction, it can be converted into a racemate (7S, 9S; 7R, 9R), thereby improving its yield. This epilation reaction is carried out in a water-soluble organic solvent such as acetone, tetrahydrofuran, and dioxane in the presence of an inorganic acid such as hydrochloric acid and perchloric acid within a temperature range from 10°C to the boiling point of the solvent used. can be done. (A-1)→() In this step, the compound of formula (A-1) is derived from daunosamine and has the following formula: The glycoside of the formula () is obtained. As the amino protecting group R′ in the above formula (10),
Protective groups that can be easily removed by hydrolysis, such as lower alkanoyl groups such as acetyl, propionyl, trifluoroacetyl; benzoyl, p
-Aromatic carbonyl groups such as nitrobenzoyl; aralkyloxycarbonyl and alkyloxycarbonyl groups such as benzyloxycarbonyl and t-butoxycarbonyl, and can be easily removed by hydrolysis as a hydroxyl protecting group R'' Protecting groups are also generally similar to the above amino protecting groups.
It can be the same group as R'. The above glycosylation reaction can be carried out by a method using an acid catalyst which is known per se, and is usually carried out using an anhydrous organic solvent such as benzene, toluene, tetrahydrofuran, dioxane, etc., preferably an aromatic hydrocarbon such as benzene, toluene, etc. Among them, acid catalysts such as aromatic sulfonic acids such as p-toluenesulfonic acid and benzenesulfonic acid; methanesulfonic acid,
This can be carried out in the presence of an alkylsulfonic acid such as butanesulfonic acid. Reaction temperature is usually 0-80
℃, preferably 20 to 40°C is advantageous. In addition, the glycal of the above formula (10) is obtained by preparing a daunosamine derivative in which the 3-amino group and 4-hydroxyl group are protected with the groups described above, in an organic solvent or without using a base such as pyridine, dimethylaniline, morpholine, It can be produced by treatment with a sulfonylating agent such as p-toluenesulfonic acid chloride, benzenesulfonic acid chloride, etc. in the presence of triethylamine etc.
54-27346). According to the above glycosylation reaction, the glycoside of formula () is usually one in which the amino sugar residue has a 1'α-bond (hereinafter referred to as 1'α-bond) and one in which the amino sugar residue has a 1'β-bond (hereinafter referred to as 1'β-bond). It is obtained as a mixture of the 1′β-isomer), but the 1′α-isomer is generally the main component. Therefore, (7S, 9S;
7R, 9R) racemate is used as a starting material, the glycoside of formula () is (7S, 9S,
1′α), (7S, 9S, 1′β), (7R, 9R, 1′α) and (7R, 9R, 1′β), but these isomers The bodies can be isolated individually by chromatography using, for example, silica gel. Note that this stereoisomer isolation may be performed after the completion of the deprotection reaction described below. ()→(1-a) This step is a deprotection reaction step for the compound of formula (), and this deprotection reaction can be carried out by a hydrolysis method known per se. This hydrolysis converts the protecting group R′ and the compound of formula () into
In addition, when R 12 is a lower alkanoyloxy group, depending on the hydrolysis conditions, the lower alkanoyl group can also be released, and R 1
It is also possible to form corresponding compounds of formula (-a) in which is OH. In this way, the anthracycline derivative represented by the above formula (-a) can be obtained in good yield. In addition,
Although the aglycone portions of the formulas shown herein are all illustrated as planar structures, these formulas include
(7S, 9S) (7R, 9R), (7S, 9R) and (7R,
9S) is used to include all steric configurations. Furthermore, R 12 produced in the above method
The compound of formula () in which R 1 represents a hydrogen atom can be converted into the corresponding compound of formula () in which R 1 represents a lower alkanoyloxy group by subjecting it to the steps (4) → (5) → (6) described above. It can be changed. The compound of formula (-a) obtained as described above can be converted into an acid addition salt by treatment with an inorganic or organic acid as described above according to a method known per se. As mentioned above, the compound of formula (-a) has excellent antitumor activity, and among them, compounds with the same configuration as daunomycin and adriamycin produced by fermentation, that is, (7S, 9S) configuration. It is particularly preferred that the glycoside has a 1'α-bond. The antitumor activity of the compound of formula (-a) provided by the present invention can be demonstrated by the experiments described below. (A) Proliferation of murine leukemia L1210 cultured cells;
and DNA synthesis and RNA synthesis inhibitory effect The compound of the present invention significantly suppresses the proliferation and nucleic acid synthesis of mouse leukemia cultured cells (L1210). For example, L1210 cells are inoculated at 5 x 10 cells/ml into RPMI 1640 medium (Rothwell Park Institute 1640) containing 20% calf serum, and at the same time, the compound of the present invention is added at concentrations of 0.1 and 0.5 μg/ml, The cells were cultured in a carbon dioxide gas incubator at 37°C, and the concentration of 50% growth inhibition relative to the control group was determined. Furthermore, 5×10 5 of the above L1210 cultured cells were added to RPMI1640 medium containing 10% calf serum.
After 1 to 2 hours of culture in a carbon dioxide gas incubator at 37°C, the compounds of the present invention were added at various concentrations, and after 15 minutes, they were further incubated with 14C .
Uridine (0.05 μCi/ml) and 14 C-thymidine (0.05 μCi/ml) were added and cultured at 37° C. for 60 minutes. A 10% trichloroacetic acid solution was added to the reaction solution to stop the reaction, and at the same time, acid-insoluble substances were precipitated, washed three times with 10 to 5% trichloroacetic acid, and then dissolved in formic acid to remove radiation in the acid-insoluble substances. Measure the activity and calculate the radioactivity uptake rate of 10% and 50% from the control group.
% and 90% uptake inhibition concentrations were determined. The results are shown in Table 1.
【表】【table】
【表】
(B) マウス白血病L1210細胞により誘起された
CDFIマウスの白血病に対する抗腫瘍性
実験腫瘍動物に対する効果は、CDF1マウスの
腹腔内へマウス白血病L1210細胞を１×105ケ／
マウス移殖し、24時間後より連日10日間本発明の
化合物を腹腔内へ投与し、対照区（生理食塩水投
与）に比較し算定した延命率（Ｔ／Ｃ，％）で求
めた。結果を第２表に示す。[Table] (B) Induced by mouse leukemia L1210 cells
Antitumor activity against leukemia in CDFI mice The effect on experimental tumor animals was determined by injecting mouse leukemia L1210 cells into the peritoneal cavity of CDF1 mice at 1×10 5 cells/
After 24 hours of transplantation into mice, the compound of the present invention was intraperitoneally administered every day for 10 days, and the survival rate (T/C, %) was calculated in comparison with a control group (physiological saline administration). The results are shown in Table 2.
【表】
以上に述べた実験結果から明らかなように、本
発明により提供される前記式（―ａ）の化合
物、殊に式（―ａ―１）の化合物は、L1210白
血病細胞および実験動物腫瘍に対して優れた抗腫
瘍活性を示す。そのうちでも、特に４―デメトキ
シ―11―デオキシ―アドリアマイシンの（7S，
9S，1′α）立体異性体の抗腫瘍活性は注目に値す
る。
本発明により提供される前記式（―ａ）の化
合物はまた、抗菌活性を有する点にいても特徴的
であり、その抗菌活性は栄養寒天培地上での各種
細菌に対する最低発育阻止濃度（M.I.C.）で示せ
ば下記第３表に示すとおりである。[Table] As is clear from the experimental results described above, the compound of formula (-a) provided by the present invention, especially the compound of formula (-a-1), can be used in L1210 leukemia cells and experimental animal tumors. It shows excellent antitumor activity against. Among them, 4-demethoxy-11-deoxy-adriamycin (7S,
The antitumor activity of the 9S, 1′α) stereoisomer is noteworthy. The compound of formula (-a) provided by the present invention is also unique in that it has antibacterial activity, and its antibacterial activity is determined by the minimum inhibitory concentration (MIC) against various bacteria on a nutrient agar medium. It is as shown in Table 3 below.
【表】
以上述べたように、本発明により提供される前
記式（―ａ）の化合物又は製薬学的に許容しう
るその酸付加塩は、優れた抗腫瘍活性を有してお
り、抗悪性腫瘍治療剤として固形癌及び腹水癌等
の措置のために使用することができる。
該活性化合物を実際に投与する場合には、一般
に注射用蒸留水又は生理食塩水に溶解して非経口
的に投与することができる。
その場合の投与方法としては動物の場合、腹腔
内注射、皮下注射、静脈又は動脈への血管内注射
及び局所投与等の注射剤として、ヒトの場合は静
脈又は動脈への血管内注射又は局所投与等の注射
剤として投与され、その投薬量は動物試験の結果
及び種々の情況を勘案して総投与量が一定量を越
えない範囲で、連続的又は間けつ的に投与するこ
とができる。しかし、その投与量は投与方法、患
者、又は被処理動物の状況例えば年令、体重、性
別、感受性、食餌、投与時間、投与方法、併用す
る薬剤、患者又はその病気の程度に応じて適宜に
変えて投与することはもちろんであり、一定の条
件の下における適量と投与回数は、上記の指針を
基として専門医の適量決定試験によつて決定され
なければならない。また、本発明の活性化合物は
グラム陽性菌に対して抗菌性を示し、グラム陽性
菌に由来する疾病治療剤として上記剤型及び投与
量にて投与することができる。その他投与回数、
剤型等は当業者であればすべて上記に述べたと同
じような注意をもつて決定することができる。
以下に製造の実施例を示し、本発明をより具体
的に説明する。
実施例 １
４―デメトキシ―11―デオキシダウノマイシン
の製造
工程Ａ：２―エチニル―２―ヒドロキシ―５―メ
トキシ―１，２，３，４―テトラヒドロナフタ
レン
無水テトラヒドロフラン（以下、THFと記
す）80mlにアセチレンを吹き込みながら、同時に
2M濃度のエチルマグネシウムブロマイドのエー
テル溶液36mlを滴下する。
以上の溶液に５―メトキシ―２―テトラロン
2.88gを加える。反応終了後、反応液を飽和塩化
アンモン水500mlを注ぎ、四塩化炭素200mlで３回
抽出を繰り返す。抽出液を水液した後、硫酸ナト
リウムで乾燥し、濃縮乾固する。得られた茶色の
油状物をベンゼン／酢酸エチル（25／１）を使用
してシリカゲル上でクロマトグラフイー処理して
目的物1.6gをアメ色のオイルとして得た。
NMRδ：60MHz，CDCl3
1.9〜2.3 （ｍ）３位 ―CH2―
2.40 （ｓ）２位 ―Ｃ≡CH
2.42 （ｓ）２位 ―OH
2.7〜3.1 （ｍ）４位 ―CH2―
3.05〜3.2 （ｍ）１位 ―CH2―
3.82 （ｓ）５位 ―OCH3
6.6〜7.35 （ｍ）６、７、８位
―Hx3
工程Ｂ：２―アセチル―２―ヒドロキシ―５―メ
トキシ―１，２，３，４―テトラヒドロナフタ
レン
上記化合物(2)を四塩化炭素10mlに溶解し、
1.5N硫酸10mlおよび酸化水銀200mgを加入後、室
温で27時間反応させた後水40mlを加え四塩化炭素
50mlで４回抽出する。抽出液を水洗した後、硫酸
ナトリウムで乾燥し、濃縮乾固する。得られた油
状物をベンゼン／酢酸エチル（20／１）を使用し
てシリカゲル上でクロマトグラフイー処理して目
的物の無色針状結晶840mgを得た。
m.p.63〜63.5℃
NMRδ：60MHz，CDCl3
1.8〜2.1 （ｍ）３位 ―CH2―
2.28 （ｓ）２位 COCH3
2.5〜3.5 （ｍ）１、４位 ―CH2―
×２
3.45 （ｓ）２位 OH
3.83 （ｓ）５位 OCH3
6.6〜7.3 （ｍ）６、７、８位
Ｈ×３
工程Ｃ：４―デメトキシ―７，11―ジデオキシダ
ウノマイシノン
工程Ｂで得られた化合物(3)230mg、無水フタル
酸230mg、塩化ナトリウム460mgおよび塩化アルミ
ニウム2.3gをよく混ぜ合わせ180℃に加熱融解さ
せる。１〜２分で均一になるがさらに５分間反応
させる。
反応混合物を飽和シユウ酸水で処理し、該水溶
液からクロロホルム30mlで５回抽出する。合わせ
た抽出液を水洗した後、硫酸ナトリウムで乾燥後
濃縮乾固する。これをベンゼン／酢酸エチル
（20／１）を使用してシリカゲル上でクロマトグ
ラフイー処理して目的物の黄色固体110mgを得
た。
m.p.208〜214℃（分解）
NMRδ：60MHz，DMSO
1.7〜2.2 （ｍ）８位 ―CH2―
2.30 （ｓ）９位 ―COCH3
2.6〜3.1 （ｍ）７、10位
―CH2―×２
5.60 （ｓ）９位 ―OH
7.38 （ｓ）11位 ―Ｈ
7.8〜8.4 （ｍ）１、２、３、４位
―Ｈ×４
12.80 （ｓ）６位 ―OH
工程Ｄ：化合物(4)のケタール化合物
化合物(4)100mgをベンゼン15mlに溶解し、エチ
レングリコール0.3mlおよびｐ―トルエンスルホ
ン酸を触媒量加え、還流下３時間反応させる。反
応液を0.02N炭酸水素ナトリウム水溶液に注ぎ、
そこから酢酸エチル40mlで３回抽出する。抽出液
を硫酸ナトリウムで乾燥後、濃縮乾固する。（該
反応は定量的に進む）
工程Ｅ：４―デメトキシ―11―デオキシダウノマ
イシノン
工程Ｄで得られたケタール化物（８―ａ）をク
ロロホルムに溶かし、0.8％（Ｗ／Ｖ）ブロムの
四塩化炭素12.6ml、水21mlおよびAIBN120mgを加
え室温で3.5時間反応させる。反応後さらに上記
ブロム溶液４mlを加えて２時間反応させる。反応
終了後反応液からブロム、四塩化炭素、クロロホ
ルムを留去する。残留物をアセトン120mlに溶解
し、8N―塩酸水21mlを加えて室温で18時間反応
させる〔ケタールの脱保護と（7S，9R；7R，
9S）→（7S，9S；7R，9R）へのエピ化〕。反応
終了後、反応液からアセトンを留去し、クロロホ
ルム25mlで２回抽出する。抽出液を水洗した後硫
酸ナトリウムで乾燥し、濃縮乾固する。
これをアセトンを使用して架橋デキストランゲ
ル（例えば、セフアデツクスLH―20：フアルマ
シヤ社製）で処理した後アセトンを留去して目的
物〔ラセミ体（7S，9R；7R，9S）とラセミ体
（7S，9S；7R，9R）の混合物〕を得た。この混
合物をベンゼン／酢酸エチル（16／１）、同
（12／１）、同（８／１）続いて同（４／１）使用
して、シリカゲル上でクロマトグラフイー処理
し、掲記化合物の立体異性体（7S，9S；7R，
9R）体の黄色固体41mgと（7S，9R；7R，9S）体
の黄色固体24mgを得た。
工程E′：４―デメトキシ―11―デオキシダウノ
マイシン（7S，9R；7R，9S）体の同（7S，
9S；7R，9R）体へのエピ化
上記の（7S，9R；7R，9S）体24mgをアセトン
15mlに溶解し、60％過塩素酸1.5mlを加え室温で
３時間反応させる。工程Ｅと同様の後処理、精製
によつて、４―デメトキシ―11―デオキシダウノ
イシン（7S，9S；7R，9R）12mgを得た。
m.p.199〜207℃（分解）
NMRδ：60MHz CDCl3
2.0〜2.5 （ｍ）８位 ―CH2―
2.44 （ｓ）９位
[Table] As described above, the compound of the formula (-a) or the pharmaceutically acceptable acid addition salt thereof provided by the present invention has excellent antitumor activity and is an antimalignant compound. It can be used as a tumor therapeutic agent to treat solid cancer, ascites cancer, etc. When the active compound is actually administered, it can generally be dissolved in distilled water for injection or physiological saline and administered parenterally. In this case, the administration method for animals is intraperitoneal injection, subcutaneous injection, intravascular injection into a vein or artery, and local administration, and in the case of humans, intravascular injection into a vein or artery or local administration. The dosage can be administered continuously or intermittently, with the total dosage not exceeding a certain amount, taking into account the results of animal studies and various circumstances. However, the dosage should be determined appropriately depending on the administration method, the condition of the patient or treated animal, such as age, body weight, sex, sensitivity, diet, administration time, administration method, concomitant drugs, and the patient or the degree of the disease. It goes without saying that the dosage may be varied, and the appropriate dose and frequency of administration under certain conditions must be determined by a specialist's appropriate dosage determination test based on the above-mentioned guidelines. Furthermore, the active compound of the present invention exhibits antibacterial properties against Gram-positive bacteria, and can be administered in the above dosage form and dosage as a therapeutic agent for diseases originating from Gram-positive bacteria. Other number of administrations,
Dosage forms and the like can be determined by those skilled in the art with the same precautions as described above. The present invention will be explained in more detail with reference to production examples below. Example 1 Production of 4-demethoxy-11-deoxydaunomycin Step A: 2-ethynyl-2-hydroxy-5-methoxy-1,2,3,4-tetrahydronaphthalene While blowing acetylene into 80ml of anhydrous tetrahydrofuran (hereinafter referred to as THF),
36 ml of a 2M solution of ethylmagnesium bromide in ether are added dropwise. 5-methoxy-2-tetralone in the above solution
Add 2.88g. After the reaction is completed, 500 ml of saturated ammonium chloride water is poured into the reaction solution, and extraction is repeated three times with 200 ml of carbon tetrachloride. The extract is diluted with water, dried over sodium sulfate, and concentrated to dryness. The resulting brown oil was chromatographed on silica gel using benzene/ethyl acetate (25/1) to obtain 1.6 g of the desired product as a candy-colored oil. NMRδ: 60MHz, CDCl 3 1.9~2.3 (m) 3rd place - CH 2 - 2.40 (s) 2nd place - C≡CH 2.42 (s) 2nd place - OH 2.7~3.1 (m) 4th place - CH 2 - 3.05~ 3.2 (m) 1st place - CH 2 - 3.82 (s) 5th place - OCH 3 6.6~7.35 (m) 6th, 7th, 8th place
-Hx3 Step B: 2-acetyl-2-hydroxy-5-methoxy-1,2,3,4-tetrahydronaphthalene Dissolve the above compound (2) in 10 ml of carbon tetrachloride,
After adding 10ml of 1.5N sulfuric acid and 200mg of mercury oxide, react at room temperature for 27 hours, then add 40ml of water and add carbon tetrachloride.
Extract 4 times with 50 ml. The extract is washed with water, dried over sodium sulfate, and concentrated to dryness. The resulting oil was chromatographed on silica gel using benzene/ethyl acetate (20/1) to obtain 840 mg of colorless needle crystals of the desired product. mp63~63.5℃ NMRδ: 60MHz, CDCl 3 1.8~2.1 (m) 3rd place - CH 2 - 2.28 (s) 2nd place COCH 3 2.5~3.5 (m) 1st and 4th place - CH 2 -
×2 3.45 (s) 2nd place OH 3.83 (s) 5th place OCH 3 6.6-7.3 (m) 6th, 7th, 8th place
H×3 Step C: 4-demethoxy-7,11-dideoxydaunomycinone 230 mg of compound (3) obtained in Step B, 230 mg of phthalic anhydride, 460 mg of sodium chloride and 2.3 g of aluminum chloride are mixed well and heated to 180°C to melt. It will become uniform in 1 to 2 minutes, but let it react for an additional 5 minutes. The reaction mixture is treated with saturated aqueous oxalic acid, and the aqueous solution is extracted five times with 30 ml of chloroform. The combined extracts were washed with water, dried over sodium sulfate, and concentrated to dryness. This was chromatographed on silica gel using benzene/ethyl acetate (20/1) to obtain 110 mg of the desired yellow solid. mp208~214℃ (decomposition) NMRδ: 60MHz, DMSO 1.7~2.2 (m) 8th place - CH 2 - 2.30 (s) 9th place - COCH 3 2.6~3.1 (m) 7th, 10th place
-CH 2 -×2 5.60 (s) 9th place -OH 7.38 (s) 11th place -H 7.8~8.4 (m) 1st, 2nd, 3rd, 4th place
-H×4 12.80 (s) 6th position -OH Step D: Ketal compound of compound (4) 100 mg of compound (4) is dissolved in 15 ml of benzene, 0.3 ml of ethylene glycol and catalytic amounts of p-toluenesulfonic acid are added, and the mixture is reacted under reflux for 3 hours. Pour the reaction solution into 0.02N sodium hydrogen carbonate aqueous solution,
From there, extract three times with 40 ml of ethyl acetate. After drying the extract with sodium sulfate, it is concentrated to dryness. (The reaction proceeds quantitatively) Step E: 4-demethoxy-11-deoxydaunomycinone The ketal compound (8-a) obtained in Step D is dissolved in chloroform, 12.6 ml of 0.8% (W/V) bromine in carbon tetrachloride, 21 ml of water and 120 mg of AIBN are added, and the mixture is reacted at room temperature for 3.5 hours. After the reaction, 4 ml of the above bromine solution was added and the reaction was continued for 2 hours. After the reaction is complete, bromine, carbon tetrachloride, and chloroform are distilled off from the reaction solution. Dissolve the residue in 120 ml of acetone, add 21 ml of 8N-hydrochloric acid, and react at room temperature for 18 hours [Deprotection of ketal (7S, 9R; 7R,
9S)→(7S, 9S; 7R, 9R)]. After the reaction is complete, acetone is distilled off from the reaction solution and extracted twice with 25 ml of chloroform. The extract is washed with water, dried over sodium sulfate, and concentrated to dryness. This is treated with a cross-linked dextran gel (e.g., Cephadex LH-20, manufactured by Pharmacia) using acetone, and the acetone is distilled off to obtain the desired products [racemic form (7S, 9R; 7R, 9S)] and racemic form (7R, 9S). 7S, 9S; 7R, 9R) was obtained. This mixture was chromatographed on silica gel using benzene/ethyl acetate (16/1), benzene/ethyl acetate (12/1), benzene/ethyl acetate (8/1) and benzene/ethyl acetate (4/1) to obtain the listed compounds. Stereoisomers (7S, 9S; 7R,
41 mg of a yellow solid of the 9R) body and 24 mg of a yellow solid of the (7S, 9R; 7R, 9S) body were obtained. Step E′: 4-demethoxy-11-deoxydaunomycin (7S, 9R; 7R, 9S)
Epimerization to 9S; 7R, 9R) body Add 24 mg of the above (7S, 9R; 7R, 9S) body to acetone.
Dissolve in 15 ml, add 1.5 ml of 60% perchloric acid, and react at room temperature for 3 hours. By post-treatment and purification similar to Step E, 12 mg of 4-demethoxy-11-deoxydaunoisin (7S, 9S; 7R, 9R) was obtained. mp199-207℃ (decomposition) NMRδ: 60MHz CDCl 3 2.0-2.5 (m) 8th place - CH 2 - 2.44 (s) 9th place
【式】
3.14 （AB）10位 ―CH2―
3.65 ７位 ―OH
4.60 （ｓ）９位 ―OH
5.36 （ｍ）７位 ―Ｈ
7.60 （ｓ）11位 ―Ｈ
7.7〜7.9 （ｍ）２、３位 ―Ｈ×２
8.2〜8.4 （ｍ）１、４位 ―Ｈ×２
13.23 （ｓ）６位 ―OH
実施例 ２
14―Ｏ―アセチル―４―デメトキシ―11―デオ
キシアドリアマイシノンの製造
工程Ａ：14―Ｏ―アセチル―４―デメトキシ―
７，11―デオキシアドリアマイシン
実施例１の工程Ｃで得られる化合物(4)110mgを
THF12mlに溶解し、NBS200mgを１時間間隔で４
回加えて、総計６時間室温で反応させる。反応液
を水200mlに注ぎ四塩化炭素100mlで２回抽出す
る。抽出液を硫酸ナトリウムで乾燥後濃縮し減圧
乾固する。これを単離精製することなくアセトン
40mlに溶解し、酢酸カリ200mgを加え室温下８時
間反応させる。反応終了後反応液を水50mlに注
ぎ、クロロホルム25mlで４回抽出し、硫酸ナトリ
ウムで乾燥後濃縮乾固する。
これをベンゼン／酢酸エチル（40／１）、同
（30／１）、同（20／１）および同（15／１）を使
用し、シリカゲル上でクロマトグラフイー処理
し、標題の化合物83mgを得た。
m.p.206〜209℃
NMRδ：100MHz CDCl3
2.0〜2.3 （ｍ）８位 ―CH2―
2.20 （ｓ）９位
[Formula] 3.14 (AB) 10th place - CH 2 - 3.65 7th place - OH 4.60 (s) 9th place - OH 5.36 (m) 7th place - H 7.60 (s) 11th place - H 7.7~7.9 (m) 2, 3rd place -Hx2 8.2~8.4 (m) 1st, 4th place -Hx2 13.23 (s) 6th position -OH Example 2 Production of 14-O-acetyl-4-demethoxy-11-deoxyadriamycinone Step A: 14-O-acetyl-4-demethoxy-
7,11-deoxyadriamycin 110 mg of compound (4) obtained in Step C of Example 1
Dissolve in 12 ml of THF and add 200 mg of NBS at 4 hour intervals.
The mixture was added twice and allowed to react at room temperature for a total of 6 hours. The reaction solution was poured into 200 ml of water and extracted twice with 100 ml of carbon tetrachloride. The extract is dried over sodium sulfate, concentrated and dried under reduced pressure. Acetone can be used without isolation and purification.
Dissolve in 40 ml, add 200 mg of potassium acetate, and react at room temperature for 8 hours. After the reaction is completed, the reaction solution is poured into 50 ml of water, extracted four times with 25 ml of chloroform, dried over sodium sulfate, and concentrated to dryness. This was chromatographed on silica gel using benzene/ethyl acetate (40/1), ethyl acetate (30/1), ethyl acetate (20/1) and ethyl acetate (15/1) to yield 83 mg of the title compound. Obtained. mp206~209℃ NMRδ: 100MHz CDCl 3 2.0~2.3 (m) 8th place - CH 2 - 2.20 (s) 9th place
【式】
2.79 （ｓ）９位 ―OH
2.8〜3.5 （ｍ）７、10位 ―CH2―×２
5.11 （ｓ）
[Formula] 2.79 (s) 9th place -OH 2.8~3.5 (m) 7th and 10th place -CH 2 -×2 5.11 (s)
【式】
7.60 （ｓ）11位 ―Ｈ
7.75〜7.9 （ｍ）２、３位 ―Ｈ×２
8.2〜8.4 （ｍ）１、４位 ―Ｈ×２
13.03 （ｓ）６位 ―OH
工程Ｂ：14―Ｏ―アセチル―４―デメトキシ―11
―デオキシアドリアマイシン
上記化合物（６―ａ）51mgをクロロホルム14ml
に溶解し、水12mlおよびAIBN16mgを加えた反応
液に0.8％（Ｗ／Ｖ）ブロムの四塩化炭素0.5mlを
室温下、１時間間隔で７回に分けて加え、９時間
反応させる。反応終了後未反応ブロム、四塩化炭
素およびクロロホルムを留去する。残留物を酢酸
エチル40mlに溶解し、0.1N―炭酸水酸ナトリウ
ム水溶液10mlを加えて室温で一昼夜撹拌する。反
応終了後分液操作し、酢酸エチル層を水洗した
後、硫酸ナトリウムで乾燥し、濃縮乾固する。乾
固物を工程Ａと同様にクロマトグラフイー処理
し、標題の化合物の7S，9S；7R，9Rラセミ体34
mgを得た。
m.p.198〜205℃（分解）
NMRδ：100MHz CDCl3
2.0〜2.6 （ｍ）８位 ―CH2―
2.19 （ｓ）９位[Formula] 7.60 (s) 11th place -H 7.75~7.9 (m) 2nd and 3rd place -H×2 8.2~8.4 (m) 1st and 4th place -H×2 13.03 (s) 6th place -OH Process B: 14-O-acetyl-4-demethoxy-11
- Deoxyadriamycin 51 mg of the above compound (6-a) in 14 ml of chloroform
To a reaction solution prepared by adding 12 ml of water and 16 mg of AIBN, 0.5 ml of 0.8% (W/V) bromine in carbon tetrachloride was added in 7 portions at 1 hour intervals at room temperature, and the mixture was allowed to react for 9 hours. After the reaction is completed, unreacted bromine, carbon tetrachloride and chloroform are distilled off. Dissolve the residue in 40 ml of ethyl acetate, add 10 ml of 0.1N aqueous sodium hydroxide solution, and stir at room temperature overnight. After the reaction is completed, the layers are separated, and the ethyl acetate layer is washed with water, dried over sodium sulfate, and concentrated to dryness. The dried product was subjected to chromatography in the same manner as in Step A to obtain the 7S, 9S; 7R, 9R racemate 34 of the title compound.
I got mg. mp198~205℃ (decomposition) NMRδ: 100MHz CDCl 3 2.0~2.6 (m) 8th place - CH 2 - 2.19 (s) 9th place
【式】
3.28 ７位 ―OH
3.22 （AB）10位 ―CH2―
4.69 （ｓ）９位 ―OH
5.25 （AB）
[Formula] 3.28 7th place - OH 3.22 (AB) 10th place - CH 2 - 4.69 (s) 9th place - OH 5.25 (AB)
【式】
5.42 （ｍ）７位 ―Ｈ
7.68 （ｓ）11位 ―Ｈ
7.75〜7.9 （ｍ）２、３位 ―Ｈ×２
8.25〜8.4 （ｍ）１、４位 ―Ｈ×２
13.40 （ｓ）６位 ―OH
IR（cm-1）
3450、2950、1750、1730、
1670、1630、1590、1480、
1420、1385、1360、1330、
1285、1270、1245、1215、
1160、1110、1100、1065、
1060、1040、1030、1010、
980、960、930、910、870、
840、830、820、795、770、
745、715。
実施例 ３
４―デメトキシ―11―デオキシダウノマイシン
の製造
工程Ａ：４―Ｏ―ｐ―ニトロベンゾイル―１，
２，３，６―テトラデオキシ―３―トリフルオ
ロアセタミド―Ｌ―リキソ―ヘキス―１―エン
ピラトス
(i) Ｎ―トリフルオロアセチルダウノサミン104
mgを無水ピリジンに溶解させた後、ｐ―ニトロ
ベンゾイルクライド300mgを加え氷冷下（約８
℃）で２時間反応させる。反応終了後反応液を
氷水100mlに注ぎ過剰の試薬をつぶす。これよ
りクロロホルム30mlで３回抽出し抽出液からピ
リジンを除去するために1N塩酸水50mlで分液
操作する。クロロホルム層を水洗し硫酸ナトリ
ウムで乾燥後濃縮する。
(ii) 濃縮物（１，４―ビス―Ｏ―ｐ―ニトロベン
ゾイルＮ―トリフルオロアセチルダウノサミン
粗製物）をアセトン10mlに溶解した後4N塩酸
水５mlを加え、室温下10時間反応させて、ｐ―
ニトロベンゾイル基を部分加水分解する。反応
終了後アセトンのみを濃縮除去し、水15mlを加
えクロロホルム10mlで３回抽出する。抽出液を
0.1N炭酸水素ナトリウム水溶液10mlで分液操
作する。クロロホルム層を水洗し硫酸ナトリウ
ムで乾燥後濃縮する。
(iii) 濃縮物（４―Ｏ―ｐ―ニトロベンゾイル―Ｎ
―トリフルオロアセチルダウノサミン粗製物）
を無水ピリジン15mlに溶解し、ｐ―トルエンス
ルホニルクロライド600mgを加え80℃で18時間
反応させる。茶褐色の反応液を氷水100mlに注
ぎ過剰の試薬をつぶす。これによりベンゼン30
mlで４回抽出し、抽出液を水洗後硫酸ナトリウ
ムで乾燥し、濃縮する。油状物をベンゼン／酢
酸エチル（25／１）を使用し、シリカゲル上で
クロマトグラフイー処理し、標題の化合物118
mgを得た。
m.p.144〜148℃；〔α〕２６ Ｄ：−100°（ｃ，0.5ア
セトン）
NMRδ：100MHz CDCl3
1.32 （ｄ）６位 ―CH3
4.36 （broad ｑ）５位 Ｈ
4.62 （td）２位 Ｈ
5.05 （ｍ）３位 Ｈ
5.66 （broad ｄ）４位 Ｈ
6.15 （broad ｄ） ―NHCOCF3
6.65 （dd）１位 Ｈ
8.15〜8.4 （ｍ）
[Formula] 5.42 (m) 7th place - H 7.68 (s) 11th place - H 7.75~7.9 (m) 2nd and 3rd place - H x 2 8.25 - 8.4 (m) 1st and 4th place - H x 2 13.40 (s ) 6th place -OH IR (cm -1 ) 3450, 2950, 1750, 1730, 1670, 1630, 1590, 1480, 1420, 1385, 1360, 1330, 1285, 1270, 1245, 1215, 1160, 1110, 1100, 1065 , 1060, 1040, 1030, 1010, 980, 960, 930, 910, 870, 840, 830, 820, 795, 770, 745, 715. Example 3 Production of 4-demethoxy-11-deoxydaunomycin Step A: 4-O-p-nitrobenzoyl-1,
2,3,6-tetradeoxy-3-trifluoroacetamide-L-lyxo-hex-1-empyratos (i) N-trifluoroacetyl daunosamine 104
After dissolving 300 mg of p-nitrobenzoylcide in anhydrous pyridine, add 300 mg of p-nitrobenzoylcide under ice cooling (approximately 8
℃) for 2 hours. After the reaction is complete, pour the reaction solution into 100 ml of ice water to crush excess reagent. This was extracted three times with 30 ml of chloroform, and in order to remove pyridine from the extract, the extract was separated with 50 ml of 1N hydrochloric acid. The chloroform layer is washed with water, dried over sodium sulfate, and concentrated. (ii) After dissolving the concentrate (1,4-bis-O-p-nitrobenzoyl N-trifluoroacetyl daunosamine crude product) in 10 ml of acetone, 5 ml of 4N hydrochloric acid was added and reacted at room temperature for 10 hours. ,p-
Partially hydrolyzes the nitrobenzoyl group. After the reaction is complete, only acetone is concentrated and removed, 15 ml of water is added, and the mixture is extracted three times with 10 ml of chloroform. extract liquid
Separate the liquid using 10 ml of 0.1N sodium bicarbonate aqueous solution. The chloroform layer is washed with water, dried over sodium sulfate, and concentrated. (iii) Concentrate (4-O-p-nitrobenzoyl-N
-Trifluoroacetyldaunosamine crude product)
Dissolve in 15 ml of anhydrous pyridine, add 600 mg of p-toluenesulfonyl chloride, and react at 80°C for 18 hours. Pour the brown reaction solution into 100ml of ice water to crush excess reagent. This results in benzene 30
ml four times, and the extract is washed with water, dried over sodium sulfate, and concentrated. The oil was chromatographed on silica gel using benzene/ethyl acetate (25/1) to yield the title compound 118.
I got mg. mp144-148℃; [α] 26 D : -100° (c, 0.5 acetone) NMRδ: 100MHz CDCl 3 1.32 (d) 6th place - CH 3 4.36 (broad q) 5th place H 4.62 (td) 2nd place H 5.05 (m) 3rd place H 5.66 (broad d) 4th place H 6.15 (broad d) -NHCOCF 3 6.65 (dd) 1st place H 8.15~8.4 (m)
【式】
工程Ｂ：４―デメトキシ―4′―Ｏ―ｐ―ニトロベ
ンゾイル―11―デオキシ―3′―Ｎ―トリフルオ
ロアセチルダウノマイシン
実施例１の方法で得られる４―デメトキシ―11
―デオキシダウノマイシノン（7S，9S；7R，
9R）体20mgと上記工程Ａで得られるグリカール
80mgをベンゼン２mlに溶解し、ｐ―トルエンスル
ホン酸触媒量を加え室温で93時間反応させる。反
応終了後反応液を0.01N炭酸水素ナトリウム水溶
液30mlに注ぎ、そこからベンゼン15mlで３回抽出
する。抽出液を水洗後硫酸ナトリウムで乾燥後濃
縮乾固する。ベンゼン／酢酸（４／１）を使用
し、シリカゲル上でクロマトグラフイー処理した
後、架橋デキストランゲル（例えば、セフアデツ
クスLH―20）上で、クロロホルム／アセトン
（１／２）を使用し、クロマトグラフイー処理
し、さらにベンゼン／酢酸エチル（４／１）を使
用し、シリカゲル上でクロマトグラフイー処理
し、標題化合物の各立体異性体をそれぞれ単離す
る。単離された粗製物をそれぞれ別個に再度上記
LH―20で処理して標題化合物の7S，9S，1′α）
体（―ａ―１）７mg、同（7S，9S，1′β）体
（―ａ―２）３mg、同（7R，9R，1′α）体（
―ａ―３）10mg及び同（7R，9R，1′β）体（
―ａ―４）３mgを得た。
（―ａ―１）：
m.p.153〜156℃；〔α〕２４ Ｄ―125゜（ｃ，0.2アセ
トン）
NMRδ：100MHz CDCl3
1.27 （ｓ）6′位 ―CH3
2.0〜2.5
（ｍ）８、2′位 ―CH2―×２
2.43 （ｓ）９位 ―COCH3
3.21 （AB）10位 ―CH2―
4.25 （ｓ）９位 ―OH
4.3〜4.7 （ｍ）3′位 ―Ｈ
4.48 （broad ｑ）5′位 ―Ｈ
5.34 （ｍ）７位 ―Ｈ
5.51 （ｍ）4′位 ―Ｈ
5.69 （ｍ）1′位 ―Ｈ
6.40
（broad ｄ） NH ｄ） NHCOCF3
7.64 （ｓ）11位 ―Ｈ
7.7〜7.9
（ｍ）２、３位 ―Ｈ×２
8.2〜8.45 （ｍ）１、４位
[Formula] Step B: 4-demethoxy-4'-O-p-nitrobenzoyl-11-deoxy-3'-N-trifluoroacetyldaunomycin 4-demethoxy-11 obtained by the method of Example 1
-Deoxydaunomycinone (7S, 9S; 7R,
9R) 20mg of glycal obtained in step A above
Dissolve 80 mg in 2 ml of benzene, add a catalytic amount of p-toluenesulfonic acid, and react at room temperature for 93 hours. After the reaction is completed, the reaction solution is poured into 30 ml of 0.01N aqueous sodium bicarbonate solution, and extracted three times with 15 ml of benzene. The extract was washed with water, dried over sodium sulfate, and concentrated to dryness. Chromatography on silica gel using benzene/acetic acid (4/1) followed by chromatography using chloroform/acetone (1/2) on cross-linked dextran gel (e.g. Sephadex LH-20). E-treatment and further chromatography on silica gel using benzene/ethyl acetate (4/1) to isolate each stereoisomer of the title compound. Each isolated crude product was added separately as above again.
7S, 9S, 1′α) of the title compound after treatment with LH-20
(-a-1) 7 mg, (7S, 9S, 1'β) (-a-2) 3 mg, (7R, 9R, 1'α) (
-a-3) 10 mg and the (7R, 9R, 1'β) form (
-a-4) 3 mg was obtained. (-a-1): mp153~156℃; [α] 24 D -125° (c, 0.2 acetone) NMRδ: 100MHz CDCl 3 1.27 (s) 6' position -CH 3 2.0~2.5
(m) 8th, 2' position - CH 2 - × 2 2.43 (s) 9th position - COCH 3 3.21 (AB) 10th position - CH 2 - 4.25 (s) 9th position - OH 4.3~4.7 (m) 3' position - H 4.48 (broad q) 5' position - H 5.34 (m) 7' position - H 5.51 (m) 4' position - H 5.69 (m) 1' position - H 6.40
(broad d) NH d) NHCOCF 3 7.64 (s) 11th place -H 7.7~7.9
(m) 2nd and 3rd place - H x 2 8.2~8.45 (m) 1st and 4th place
【式】
13.33 （ｓ）６位 ―OH
（―ａ―２）：
m.p.142〜145℃；〔α〕２４ Ｄ＋87.5゜（ｃ，0.2アセ
トン）
NMRδ：100MHz CDCl3
1.07 （ｄ）6′位 ―CH3
1.7〜2.6
（ｍ）８位、2′位 ―CH2×２
2.39 （ｓ）９位 ―COCH3
3.27 （broad ｓ）10位 ―CH2―
3.84（broad ｑ）５位 ―Ｈ
4.2〜4.6 （ｍ）3′位 ―Ｈ
4.74 （broad ｓ）９位 ―OH
5.15 （dd）1′位 ―Ｈ
5.32 （ｍ）4′位 ―Ｈ
5.66 （ｍ）７位 ―Ｈ
6.54 （broad）ｄ NHCOCF3
7.61 （Ｓ）11位 ―Ｈ
7.75〜7.9
（ｍ）２、３位 ―Ｈ×２
8.1〜8.4 （ｍ）
[Formula] 13.33 (s) 6th position -OH (-a-2): mp142~145℃; [α] 24 D +87.5° (c, 0.2 acetone) NMRδ: 100MHz CDCl 3 1.07 (d) 6' position ―CH3 1.7～2.6
(m) 8th, 2′ - CH 2 ×2 2.39 (s) 9th - COCH 3 3.27 (broad s) 10th - CH 2 - 3.84 (broad q) 5th - H 4.2~4.6 (m) 3 ′ position - H 4.74 (broad s) 9th position - OH 5.15 (dd) 1' position - H 5.32 (m) 4' position - H 5.66 (m) 7th position - H 6.54 (broad) d NHCOCF 3 7.61 (S) 11th place - H 7.75-7.9
(m) 2nd and 3rd place - H x 2 8.1~8.4 (m)
【式】 ―Ｈ×２
13.36 （ｓ）６位 OH
（―ａ―３）：
m.p.148〜152℃；〔α〕２５ Ｄ−225゜（Ｃ，0.2アセ
トン）
NMRδ：100MHz CDCl3
1.26 （ｄ）6′位 ―CH3
1.6〜2.7
（ｍ）８位、2′位 ―CH2―×２
2.39 （ｓ）９位 ―COCH3
3.24 （broad ｓ）10位 ―CH2―
4.52 （ｓ）９位 ―OH
4.45〜4.8 （ｍ）3′位 ―Ｈ
4.73 （broad ｑ）5′位 ―Ｈ
5.44 （ｍ）4′位 ―Ｈ
5.5〜5.7
（ｍ）７、1′位 ―Ｈ×２
6.62 （broad ｄ） ―NHCOCF3
7.61 （ｓ）11位 ―Ｈ
7.75〜7.95
（ｍ）２、３位 ―Ｈ×２
8.2〜8.4 （ｍ）
[Formula] -H x 2 13.36 (s) 6th position OH (-a-3): mp148~152℃; [α] 25 D -225° (C, 0.2 acetone) NMRδ: 100MHz CDCl 3 1.26 (d) 6 ’ position ―CH 3 1.6～2.7
(m) 8th place, 2′ place - CH 2 - × 2 2.39 (s) 9th place - COCH 3 3.24 (broad s) 10th place - CH 2 - 4.52 (s) 9th place - OH 4.45~4.8 (m) 3 ' position - H 4.73 (broad q) 5' position - H 5.44 (m) 4' position - H 5.5~5.7
(m) 7th, 1′ position - H x 2 6.62 (broad d) -NHCOCF 3 7.61 (s) 11th place - H 7.75~7.95
(m) 2nd and 3rd place - H x 2 8.2~8.4 (m)
【式】 ―Ｈ×２
13.43 （ｓ）６位 ―OH
（―ａ―４）：
m.p.190〜195℃；〔α〕２５ Ｄ―137.5゜（ｃ，0.2アセ
トン）
NMRδ：100MHz CDCl3
1.32 （ｄ）6′位 ―CH3
1.6〜2.85
（ｍ）８位、2′位 ―CH2―×２
3.17 （AB）10位 ―CH2―
4.01 （broad ｑ）5′位 ―Ｈ
4.25〜4.6 （ｍ）3′位 ―Ｈ
4.55 （ｓ）９位 ―OH
5.20 （dd）1′位 ―Ｈ
5.3〜5.45
（ｍ）７、４位 ―Ｈ×２
6.59 （broad ｄ） ―NHCOCF3
7.57 （ｓ）11位 ―Ｈ
7.7〜7.9 （ｍ）２、３位 ―Ｈ×２
8.15〜8.4 （ｍ）
[Formula] -H×2 13.43 (s) 6th position -OH (-a-4): mp190~195℃; [α] 25 D -137.5° (c, 0.2 acetone) NMRδ: 100MHz CDCl 3 1.32 (d) 6′ position - CH 3 1.6~2.85
(m) 8th, 2' position - CH 2 - x 2 3.17 (AB) 10th - CH 2 - 4.01 (broad q) 5' position - H 4.25~4.6 (m) 3' position - H 4.55 (s) 9th place -OH 5.20 (dd) 1' place -H 5.3~5.45
(m) 7th and 4th place - H x 2 6.59 (broad d) - NHCOCF 3 7.57 (s) 11th place - H 7.7~7.9 (m) 2nd and 3rd place - H x 2 8.15~8.4 (m)
【式】 ―Ｈ×２
13.25 （ｓ）６位 ―OH
工程Ｃ：４―デメトキシ―11―デオキシダウノマ
イシン
Ｎ―トリフルオロアセチル―4′―Ｏ―ｐ―ニト
ロベンゾイル―ダウノマイシン（7S，9S，
1′α）（―ａ―１）12mgをメタノールに溶解
し、10％炭酸カリ水溶液１mlを加え氷冷（約８
℃）下12時間反応させる。反応後水15mlを加え、
クロロホルム10mlで４回抽出する。クロロホルム
層から0.5％酢酸水５mlづつ４回で酸転し、酸転
液を1N炭酸水素ナトリウム水溶液で中和した
後、再度クロロホルムで抽出する。抽出液を硫酸
ナトリウムで乾燥後濃縮乾固する。乾固物をジク
ロルメタン／ｔ―ブタノール（１／20）で溶解後
凍結乾燥し、標題化合物の（7S，9S，1′α）体
（１―ａ―1′―１）7.5mgを黄色粉末として得た。
以下同様に処理し、それぞれ、
（―ａ―２）7.3mgから標題化合物の（7S，
9S，1′β）体（―ａ―1′―２）を4.2mg、（―
ａ―３）11mgから標題化合物の（7R，9R，
1′α）体（―ａ―1′―３）を6.5mg、（―ａ―
４）6.3mgから標題化合物の（7R，9R，1′β）体
（―ａ―1′―４）を3.6mg得た。
（―ａ―1′―１）：
m.p.202〜212℃（分解）；〔α〕２４ Ｄ＋50゜（ｃ，
0.01メタノール）
FDMS：MH+482
NMRδ：100MHz CDCl3
1.28 （ｄ）6′位 CH3
1.6〜2.6
（ｍ）８位、2′位 ―CH2―×２
2.39 （ｓ）９位 ―COCH3
3.0〜3.2 （ｍ）3′位 ―Ｈ
3.24 （AB）10位 ―CH2―
3.44 （ｍ）4′位 ―Ｈ
4.28 （broadq）5′位 ―Ｈ
5.36 （ｍ）７位 ―Ｈ
5.55 （ｍ）1′位 ―Ｈ
7.64 （ｓ）11位 ―Ｈ
7.75〜7.95
（ｍ）２、３位 ―Ｈ×２
8.25〜8.45
（ｍ）１、４位 ―Ｈ×２
IR（cm-1）
3450、2910、1705、1665、1630、
1590、1515、1480、1455、1420、
1385、1355、1325、1300、1275、
1250、1200、1115、1005、980、
940、875、825、795、770、715。
（―ａ―1′―２）：
m.p.160〜172℃（分解）；〔α〕２２ Ｄ＋500゜（ｃ，
0.1メタノール）
FDMS：MH+482
NMRδ：100MHz CDCl3
1.25 （ｄ）6′位 ―CH3
1.55〜2.7
（ｍ）８位、2′位 ―CH2―×２
2.49 （ｓ）９位 ―COCH3
2.95〜3.2 （ｍ）3′位 ―Ｈ
3.3〜3.45 10位 ―CH2―
4′位 ―Ｈ
3.60 （broad ｑ）5′位 ―Ｈ
5.00 （dd）1′位 ―Ｈ
5.68 （ｍ）７位 ―Ｈ
7.61 （ｓ）11位 ―Ｈ
7.75〜7.95
（ｍ）２、３位 ―Ｈ×２
8.2〜8.4
（ｍ）１、４位 ―Ｈ×２
IR（cm-1）
3400、2900、1705、1670、1630
1590、1480、1420、1385、1360、
1330、1300、1275、1255、1205、1165、
1115、1060、980、920、870、830、
775、720。
（―ａ―1′―３）：
m.p.180〜195℃（分解）；〔α〕２６ Ｄ−150゜（ｃ，
0.1メタノール）
FDMS：MH+482
NMRδ：100MHz CDCl3
1.36 （ｄ）6′位 ―CH3
1.6〜2.5
（ｍ）８位、2′位 ―CH2―×２
2.40 （ｓ）９位 ―COCH3
2.9〜3.2 （ｍ）3′位 ―Ｈ
3.21 （AB）10位 ―CH2―
3.48 （ｍ）4′位 ―Ｈ
4.11 （broad ｑ）5′位 ―Ｈ
5.32 （ｍ）７位 ―Ｈ
5.50 （ｍ）1′位 ―Ｈ
7.65 （ｓ）11位―Ｈ
7.75〜7.9
（ｍ）２、３位 ―Ｈ×２
8.25〜8.45
（ｍ）１、４位 ―Ｈ×２
IR（cm-1）
3450、2900、1710、1670、1630、
1590、1480、1420、1385、1360、
1330、1300、1270、1250、1200、
1160、1120、1080、1010、980、
930、875、790、770、715。
（―ａ―1′―４）：
m.p185〜195℃（分解）；〔α〕２２ Ｄ―400゜（ｃ，
0.1メタノール）
FDMS：MH+482
NMRδ±100MHz CDCl3
1.39 （ｄ）6′位 ―CH3
1.35〜2.85
（ｍ）８位、2′位 ―CH2×４
2.42 （ｓ）９位 ―COCH3
2.9〜3.2 （ｍ）3′位 ―Ｈ
3.15 （AB）10位 ―CH2―
3.38 （ｍ）4′位 ―Ｈ
3.66 （broad ｑ）5′位 ―Ｈ
5.00 （dd）1′位 ―Ｈ
5.33 （ｍ）７位 ―Ｈ
7.64 （ｓ）11位 ―Ｈ
7.7〜7.9 （ｍ）２、３位 ―Ｈ×２
8.2〜8.4 （ｍ）１、４位 ―Ｈ×２
IR（cm-1）
3450、2900、1710、1670、1630、
1590、1480、1420、1390、1360、
1330、1300、1280、1255、1210、
1170、1130、1110、1065、1025、
985、920、870、830、790、780、
720。
実施例 ４
４―デメトキシ―11―デオキシドリアマイシン
の製造
工程Ａ：14―Ｏ―アセチル―４―デメトキシ―
4′―Ｏ―ｐ―ニトロベンゾイル―11―デオキシ
―3′―Ｎ―トリフルオロアセチルアドリアマイ
シン
実施例２の方法によつて得られた14―Ｏ―アセ
チル―４―デメトキシ―11―デオキシアドリアマ
イシノン（7S，9S；7R，9R）体および実施例３
の工程Ａで得たグリカール120mgをジクロルメタ
ン12mlに溶解し、ｐ―トルエンスルホン酸触媒量
を加え室温で75時間反応させる。反応終了後反応
液を0.01N炭酸水素ナトリウム水溶液10ml中に注
ぎ、そこからジクロルメタン10mlで２回抽出す
る。抽出液を水洗後、硫酸ナトリウムで乾燥し濃
縮乾固する。
実施例３の工程Ｂの精製法と同様に処理し、標
題化合物の（7S，9S，1′α）体（―ｂ―１）
10mg、同（7R，9R，1′α）体（―ｂ―２）
10.7mgを得た。
（―ｂ―１）：
m.p.154〜157℃；〔α〕２５ Ｄ−125゜（ｃ，0.2アセ
トン）
NMRδ：100MHz CDCl3
1.31 （ｄ）6′位 ―CH3
1.9〜2.7
（ｍ）８位、2′位 ―CH2―×２
2.22 （ｓ） OCOCH3
3.31 （AB）10位 ―CH2―
4.41 （ｓ）９位 ―OH
4.3〜4.7 （ｍ）3′位 ―Ｈ
4.45 （broad ｑ）5′位 ―Ｈ
5.24 （AB）[Formula] -H x 2 13.25 (s) 6th position -OH Step C: 4-demethoxy-11-deoxydaunomycin N-trifluoroacetyl-4'-O-p-nitrobenzoyl-daunomycin (7S, 9S,
Dissolve 12 mg of 1'α) (-a-1) in methanol, add 1 ml of 10% potassium carbonate aqueous solution, and cool on ice (approx.
℃) and incubate for 12 hours. After the reaction, add 15ml of water,
Extract 4 times with 10 ml of chloroform. The chloroform layer is acid inverted using 5 ml portions of 0.5% acetic acid water four times, and the acid inverted solution is neutralized with 1N aqueous sodium bicarbonate solution, and then extracted again with chloroform. The extract was dried over sodium sulfate and concentrated to dryness. The dried product was dissolved in dichloromethane/t-butanol (1/20) and lyophilized to obtain 7.5 mg of the (7S, 9S, 1'α) form (1-a-1'-1) of the title compound as a yellow powder. Obtained. The following treatments were carried out in the same manner, and the title compound (7S,
4.2 mg of 9S, 1′β) form (-a-1′-2), (-
a-3) From 11 mg of the title compound (7R, 9R,
6.5 mg of 1′α) form (-a-1′-3), (-a-
4) 3.6 mg of the (7R, 9R, 1'β) form (-a-1'-4) of the title compound was obtained from 6.3 mg. (-a-1'-1): mp202~212℃ (decomposition); [α] 24 D +50゜(c,
0.01 methanol) FDMS: MH + 482 NMRδ: 100MHz CDCl 3 1.28 (d) 6′ position CH 3 1.6-2.6
(m) 8th place, 2' place - CH 2 - × 2 2.39 (s) 9th place - COCH 3 3.0~3.2 (m) 3' place - H 3.24 (AB) 10th place - CH 2 - 3.44 (m) 4 ' position - H 4.28 (broadq) 5' position - H 5.36 (m) 7th position - H 5.55 (m) 1' position - H 7.64 (s) 11th position - H 7.75~7.95
(m) 2nd and 3rd place - H x 2 8.25-8.45
(m) 1st, 4th place - H x 2 IR (cm -1 ) 3450, 2910, 1705, 1665, 1630, 1590, 1515, 1480, 1455, 1420, 1385, 1355, 1325, 1300, 1275, 1250, 1200 , 1115, 1005, 980, 940, 875, 825, 795, 770, 715. (-a-1'-2): mp160-172℃ (decomposition); [α] 22 D +500゜(c,
0.1 methanol) FDMS: MH + 482 NMRδ: 100MHz CDCl 3 1.25 (d) 6′ position - CH 3 1.55-2.7
(m) 8th place, 2' place - CH 2 - × 2 2.49 (s) 9th place - COCH 3 2.95~3.2 (m) 3' place - H 3.3~3.45 10th place - CH 2 - 4' place - H 3.60 (broad q) 5' position - H 5.00 (dd) 1' position - H 5.68 (m) 7th place - H 7.61 (s) 11th place - H 7.75~7.95
(m) 2nd and 3rd place - H x 2 8.2~8.4
(m) 1st, 4th place - H×2 IR (cm -1 ) 3400, 2900, 1705, 1670, 1630 1590, 1480, 1420, 1385, 1360, 1330, 1300, 1275, 1255, 1205, 1165, 1115, 1060, 980, 920, 870, 830, 775, 720. (-a-1'-3): mp180-195℃ (decomposition); [α] 26 D -150゜(c,
0.1 methanol) FDMS: MH + 482 NMRδ: 100MHz CDCl 3 1.36 (d) 6′ position - CH 3 1.6 to 2.5
(m) 8th place, 2' place - CH 2 - × 2 2.40 (s) 9th place - COCH 3 2.9~3.2 (m) 3' place - H 3.21 (AB) 10th place - CH 2 - 3.48 (m) 4 ’ position - H 4.11 (broad q) 5' position - H 5.32 (m) 7th position - H 5.50 (m) 1' position - H 7.65 (s) 11th position - H 7.75~7.9
(m) 2nd and 3rd place - H x 2 8.25-8.45
(m) 1st, 4th place - H x 2 IR (cm -1 ) 3450, 2900, 1710, 1670, 1630, 1590, 1480, 1420, 1385, 1360, 1330, 1300, 1270, 1250, 1200, 1160, 1120 , 1080, 1010, 980, 930, 875, 790, 770, 715. (-a-1'-4): m.p185-195℃ (decomposition); [α] 22 D -400゜(c,
0.1 methanol) FDMS: MH + 482 NMRδ±100MHz CDCl 3 1.39 (d) 6′ position - CH 3 1.35 to 2.85
(m) 8th place, 2' place - CH 2 ×4 2.42 (s) 9th place - COCH 3 2.9~3.2 (m) 3' place - H 3.15 (AB) 10th place - CH 2 - 3.38 (m) 4' -H 3.66 (broad q) 5' -H 5.00 (dd) 1' -H 5.33 (m) 7th - H 7.64 (s) 11th - H 7.7~7.9 (m) 2nd and 3rd -H ×2 8.2~8.4 (m) 1st, 4th place - H × 2 IR (cm -1 ) 3450, 2900, 1710, 1670, 1630, 1590, 1480, 1420, 1390, 1360, 1330, 1300, 1280, 1255, 1210, 1170, 1130, 1110, 1065, 1025, 985, 920, 870, 830, 790, 780, 720. Example 4 Production of 4-demethoxy-11-deoxydriamycin Step A: 14-O-acetyl-4-demethoxy-
4'-O-p-nitrobenzoyl-11-deoxy-3'-N-trifluoroacetyladriamycin 14-O-acetyl-4-demethoxy-11-deoxyadriamycinone (7S, 9S; 7R, 9R) obtained by the method of Example 2 and Example 3
120 mg of the glycal obtained in Step A of is dissolved in 12 ml of dichloromethane, a catalytic amount of p-toluenesulfonic acid is added, and the mixture is allowed to react at room temperature for 75 hours. After the reaction is completed, the reaction solution is poured into 10 ml of 0.01N aqueous sodium bicarbonate solution, and extracted twice with 10 ml of dichloromethane. The extract is washed with water, dried over sodium sulfate, and concentrated to dryness. Treated in the same manner as the purification method in Step B of Example 3, the (7S, 9S, 1'α) form (-b-1) of the title compound was obtained.
10 mg, (7R, 9R, 1′α) form (-b-2)
Obtained 10.7mg. (-b-1): mp154~157℃; [α] 25 D -125° (c, 0.2 acetone) NMRδ: 100MHz CDCl 3 1.31 (d) 6' position -CH 3 1.9~2.7
(m) 8th place, 2' position - CH 2 - × 2 2.22 (s) OCOCH 3 3.31 (AB) 10th place - CH 2 - 4.41 (s) 9th place - OH 4.3~4.7 (m) 3' position - H 4.45 (broad q) 5′ position -H 5.24 (AB)
【式】
5.40 （ｍ）７位 ―Ｈ
5.50 （ｍ）4′位 ―Ｈ
5.70 （ｍ）1′位 ―Ｈ
6.30
（broad ｄ） ―NH―COCF3
7.69 （ｓ）11位 ―Ｈ
7.75〜7.95
（ｍ）２、３位 ―Ｈ×２
8.2〜8.45 （ｍ）
[Formula] 5.40 (m) 7th position - H 5.50 (m) 4' position - H 5.70 (m) 1' position - H 6.30
(broad d) -NH-COCF 3 7.69 (s) 11th place -H 7.75-7.95
(m) 2nd and 3rd place - H x 2 8.2~8.45 (m)
【式】
13.38 （ｓ）６位 ―OH
（―ｂ―２）：
m.p.155〜160℃；〔α〕２５ Ｄ−255゜（ｃ，0.2アセ
トン）
NMRδ：100MHz CDCl3
1.26 （ｄ）6′位 ―CH3
1.8〜2.8
（ｍ）８位、2′位 ―CH2―×２
2.20 （ｓ） OCOCH3
3.31 （broad ｓ）10位 ―CH2―
4.4〜4.85 （ｍ）3′位 ―Ｈ
4.72 （broad ｑ）5′位 ―Ｈ
4.62 （ｓ）９位 ―OH
5.21
（AB） ―CO―CH2―OCOCH3
5.41 （ｍ）4′位 ―Ｈ
5.5〜5.65
（ｍ）７位、1′位 ―Ｈ×２
6.52 （broad ｄ） NH―COCF3
7.63 （ｓ）11位 ―Ｈ
7.75〜7.95
（ｍ）２、３位 ―Ｈ×２
8.2〜8.4 （ｍ）
[Formula] 13.38 (s) 6th position -OH (-b-2): mp155~160℃; [α] 25 D -255° (c, 0.2 acetone) NMRδ: 100MHz CDCl 3 1.26 (d) 6' position - CH3 1.8~2.8
(m) 8th place, 2' position - CH 2 - × 2 2.20 (s) OCOCH 3 3.31 (broad s) 10th place - CH 2 - 4.4~4.85 (m) 3' position - H 4.72 (broad q) 5' Place -H 4.62 (s)9th place -OH 5.21
(AB) ―CO―CH 2 ―OCOCH 3 5.41 (m) 4′ position ―H 5.5~5.65
(m) 7th place, 1' place - H x 2 6.52 (broad d) NH-COCF 3 7.63 (s) 11th place - H 7.75~7.95
(m) 2nd and 3rd place - H x 2 8.2~8.4 (m)
【式】 ―Ｈ×２
13.46 （ｓ）６位 ―OH
工程Ｂ：４―デメトキシ―11―デオキシアドリア
マイシン
(i) 工程Ａで得られた（―ｂ―１）12.3mgをメ
タノール６mlに溶解し、10％炭酸カリ水溶液
0.06mlを加え０℃で３時間反応させる。反応終
了後水30mlを加えクロロホルム10mlで３回抽出
し、抽出液を水洗後硫酸ナトリウムで乾燥し濃
縮乾固する。本乾固物は、Ｎ―トリフルオロア
セチル―４―デメトキシ―11―デオキシアドリ
アマイシン（7S，9S，1′α）体の粗製物であ
る。
(ii) 上記乾固物をジクロルメタン３mlに溶解し、
トリエトキシメタン1.2mlおよびｐ―トルエン
スルホン酸触媒量を加え室温で2.5時間反応さ
せる。反応終了後0.1N炭酸水素ナトリウム水
溶液15mlを加え中和後ジクロルメタンで抽出す
る。抽出後を硫酸ナトリウムで乾燥後濃縮乾固
する。
(iii) 該乾固物をメタノール４mlに溶解し、10％炭
酸カリ水溶液１mlを加え氷冷（約８℃）下16時
間反応させる。反応終了後水15mlを加えてクロ
ロホルムで抽出する。抽出液を１％酢酸水で酸
転処理する（この時、オルソフオルメートは脱
離する）。酸転液を吸着用樹脂（例えば、アン
バーライトXAD―２：ロームアンドハース社
製）に吸着させた後、アセトン／0.0001N塩酸
水（20／80）、同（30／70）、同（40／60）を使
用し段階的に脱着処理する。溶出液のアセトン
のみを留去し、凍結乾燥し、４―デメトキシ―
11―デオキシアドリアマイシンの（7S，9S，
1′α）体（―ａ―1″―１）の塩酸塩3.0mgを
黄色の粉末として得た。
同様に、工程Ａで得られた（―ｂ―２）9.8
mgを処理し、４―デメトキシ―11―デオキシアド
リアマイシンの（7R，9R，1′α）体（―ａ―
1″―２）塩酸塩2.5mgを得た。
（―ａ―1″―１）塩酸塩：
m.p.158〜170℃（分解）；〔α〕２４ Ｄ＋75゜（ｃ，
0.1水）
FDMS MH+498
NMRδ：100MHz D2O
1.80 （ｄ）6′位 ―CH3
2.4〜2.9
（ｍ）８位、2′位 ―CH2―×２
3.45 （broad ｓ）10位 ―CH2―
4.1〜4.4 （ｍ）3′位 ―Ｈ
4.33 （ｍ）4′位 ―Ｈ
4.66 （broad ｑ）5′位 ―Ｈ
5.30 （ｓ）[Formula] -H x 2 13.46 (s) 6th position -OH Step B: 4-demethoxy-11-deoxyadriamycin (i) Dissolve 12.3 mg of (-b-1) obtained in Step A in 6 ml of methanol, 10% potassium carbonate aqueous solution
Add 0.06ml and react at 0°C for 3 hours. After the reaction is complete, add 30 ml of water and extract three times with 10 ml of chloroform. The extract is washed with water, dried over sodium sulfate, and concentrated to dryness. This dried product is a crude product of N-trifluoroacetyl-4-demethoxy-11-deoxyadriamycin (7S, 9S, 1′α). (ii) Dissolve the above dry matter in 3 ml of dichloromethane,
Add 1.2 ml of triethoxymethane and a catalytic amount of p-toluenesulfonic acid, and react at room temperature for 2.5 hours. After the reaction is complete, add 15 ml of 0.1N aqueous sodium bicarbonate solution to neutralize, and then extract with dichloromethane. The extracted product is dried over sodium sulfate and concentrated to dryness. (iii) Dissolve the dried product in 4 ml of methanol, add 1 ml of 10% aqueous potassium carbonate solution, and react for 16 hours under ice cooling (about 8° C.). After the reaction is complete, add 15 ml of water and extract with chloroform. The extract is subjected to acid inversion treatment with 1% aqueous acetic acid (at this time, the orthofluormate is eliminated). After adsorbing the acid transfer liquid on an adsorption resin (for example, Amberlite /60) to perform the stepwise desorption process. Only the acetone in the eluate was distilled off, lyophilized, and 4-demethoxy-
11-deoxyadriamycin (7S, 9S,
3.0 mg of hydrochloride of the 1′α) form (-a-1″-1) was obtained as a yellow powder. Similarly, (-b-2) 9.8 obtained in Step A
mg of 4-demethoxy-11-deoxyadriamycin (7R, 9R, 1′α) form (-a-
1″-2) Obtained 2.5 mg of hydrochloride. (-a-1″-1) Hydrochloride: mp158-170°C (decomposition); [α] 24 D +75° (c,
0.1 water) FDMS MH + 498 NMRδ: 100MHz D 2 O 1.80 (d) 6′ position - CH 3 2.4-2.9
(m) 8th, 2' position - CH 2 - x 2 3.45 (broad s) 10th - CH 2 - 4.1~4.4 (m) 3' position - H 4.33 (m) 4' position - H 4.66 (broad q ) 5′ position - H 5.30 (s)
【式】
5.94 （ｍ）1′位 ―Ｈ
7.53 （ｓ）11位 ―Ｈ
8.2〜8.5
（ｍ）１、２、３、４位 ―Ｈ×４
IR（cm-1）
3400、2900、1720、1670、1630、
1590、1510、1480、1420、1385、
1360、1330、1300、1275、1250、
1200、1115、1080、1060、1010、
980、940、910、875、825、770、
715。
（―ａ―1″―２）塩酸塩：
m.p.145〜155℃（分解）；〔α〕２５ Ｄ−125゜（ｃ，
0.1水）
FDMS MH+498
NMRδ：100MHz D2O
1.73 （ｄ）6′位 ―CH3
2.3〜3.2
（ｍ）８位、2′位 ―CH2―×２
3.50 （broad ｓ）10位 ―CH2―
4.1〜4.3 （ｍ）3′位 ―Ｈ
4.32 （ｍ）4′位 ―Ｈ
4.84 （broad ｑ）5′位 ―Ｈ
5.33 （ｓ）[Formula] 5.94 (m) 1' position - H 7.53 (s) 11th position - H 8.2~8.5
(m) 1st, 2nd, 3rd, 4th place - H x 4
IR (cm -1 ) 3400, 2900, 1720, 1670, 1630, 1590, 1510, 1480, 1420, 1385, 1360, 1330, 1300, 1275, 1250, 1200, 1115, 1080, 1060, 1010, 980, 940, 910, 875, 825, 770, 715. (-a-1''-2) Hydrochloride: mp145-155℃ (decomposition); [α] 25 D -125゜(c,
0.1 water) FDMS MH + 498 NMRδ: 100MHz D 2 O 1.73 (d) 6′ position - CH 3 2.3~3.2
(m) 8th, 2' position - CH 2 - x 2 3.50 (broad s) 10th - CH 2 - 4.1~4.3 (m) 3' position - H 4.32 (m) 4' position - H 4.84 (broad q ) 5′ position - H 5.33 (s)
【式】
5.47 （ｍ）７位 ―Ｈ
5.91 （ｍ）1′位 ―Ｈ
7.48 （ｓ）11位 ―Ｈ
8.2〜8.5
（ｍ）１、２、３、４位 ―Ｈ×４
IR（cm-1）
3450、2900、1720、1670、1630、
1590、1480、1425、1390、1365、
1330、1300、1280、1255、1195、
1110、1075、1010、985、935、
910、830、790、770、715。[Formula] 5.47 (m) 7th place - H 5.91 (m) 1' position - H 7.48 (s) 11th place - H 8.2~8.5
(m) 1st, 2nd, 3rd, 4th place - H x 4
IR (cm -1 ) 3450, 2900, 1720, 1670, 1630, 1590, 1480, 1425, 1390, 1365, 1330, 1300, 1280, 1255, 1195, 1110, 1075, 1010, 985, 935, 910, 830, 790, 770, 715.
Claims (1)
示されるアントラサイクリン誘導体又はその酸付
加塩である化合物。 ２ ４―デメトキシ―11―デオキシダウノマイシ
ン又はその酸付加塩である特許請求の範囲第１項
記載の化合物。 ３ ４―デメトキシ―11―デオキシアドリアマイ
シン又はその酸付加塩である特許請求の範囲第１
項記載の化合物。 ４ 該アンスラサシクリン誘導体が（7S，9S）
立体配置を有する特許請求の範囲第２または３項
記載の化合物。 ５ 該アミノ糖残基が1′α結合を有する特許請求
の範囲第４項記載の化合物。[Claims] 1. General formula A compound which is an anthracycline derivative or an acid addition salt thereof represented by the formula, wherein R 1 represents a hydrogen atom or a hydroxyl group. 2. The compound according to claim 1, which is 4-demethoxy-11-deoxydaunomycin or an acid addition salt thereof. 3 Claim 1 which is 4-demethoxy-11-deoxyadriamycin or an acid addition salt thereof
Compounds described in Section. 4 The anthracycline derivative is (7S, 9S)
The compound according to claim 2 or 3, which has a steric configuration. 5. The compound according to claim 4, wherein the amino sugar residue has a 1'α bond.
Priority Applications (16)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP55130645A JPS5756494A (en) | 1980-09-22 | 1980-09-22 | New anthracyclin derivative |
| US06/300,874 US4355026A (en) | 1980-09-22 | 1981-09-11 | 4-Demethoxy,11-deoxy anthracycline derivatives |
| DE8181107374T DE3163896D1 (en) | 1980-09-22 | 1981-09-17 | Novel anthracycline derivative, process for production thereof, and pharmaceutical composition comprising said compound |
| EP83101145A EP0086430B1 (en) | 1980-09-22 | 1981-09-17 | Anthracyclinone derivatives and process for their production |
| DE8383101145T DE3172856D1 (en) | 1980-09-22 | 1981-09-17 | Anthracyclinone derivatives and process for their production |
| EP81107374A EP0049403B1 (en) | 1980-09-22 | 1981-09-17 | Novel anthracycline derivative, process for production thereof, and pharmaceutical composition comprising said compound |
| ES505656A ES8302733A1 (en) | 1980-09-22 | 1981-09-21 | Novel anthracycline derivative, process for production thereof, and pharmaceutical composition comprising said compound. |
| PH26235A PH18087A (en) | 1980-09-22 | 1981-09-21 | Novel anthracycline derivative and pharmaceutical composition comprising said compound |
| DK418581A DK154419C (en) | 1980-09-22 | 1981-09-21 | ANTHRACYCLIN DERIVATIVES AND ANALOGY PROCEDURE FOR THE PREPARATION OF 4-DEMETHOXY-11-DEOXYADRIAMYCINE (7S, 9S, 1'ALFA ISOMER). |
| CA000386277A CA1177070A (en) | 1980-09-22 | 1981-09-21 | Anthracycline derivatives |
| AU75532/81A AU542707B2 (en) | 1980-09-22 | 1981-09-21 | Anthracycline derivatives |
| ZA816564A ZA816564B (en) | 1980-09-22 | 1981-09-22 | Novel anthracycline derivative,process for production thereof,and pharmaceutical composition comprising said compound |
| ES514919A ES8306765A1 (en) | 1980-09-22 | 1982-08-11 | Novel anthracycline derivative, process for production thereof, and pharmaceutical composition comprising said compound. |
| PH28790A PH18162A (en) | 1980-09-22 | 1983-04-18 | Process for production of 4-demethoxy-7,11-di-deoxy-daunomycinone |
| PH29674A PH18633A (en) | 1980-09-22 | 1983-10-07 | Novel antrancyclinone derivative |
| CA000456962A CA1196914A (en) | 1980-09-22 | 1984-06-19 | Anthracycline derivatives and aglycone intermediates thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP55130645A JPS5756494A (en) | 1980-09-22 | 1980-09-22 | New anthracyclin derivative |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP13294583A Division JPS6033820B2 (en) | 1983-07-22 | 1983-07-22 | Novel anthracycline derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS5756494A JPS5756494A (en) | 1982-04-05 |
| JPS6121559B2 true JPS6121559B2 (en) | 1986-05-27 |
Family
ID=15039201
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP55130645A Granted JPS5756494A (en) | 1980-09-22 | 1980-09-22 | New anthracyclin derivative |
Country Status (10)
| Country | Link |
|---|---|
| US (1) | US4355026A (en) |
| EP (2) | EP0049403B1 (en) |
| JP (1) | JPS5756494A (en) |
| AU (1) | AU542707B2 (en) |
| CA (1) | CA1177070A (en) |
| DE (1) | DE3163896D1 (en) |
| DK (1) | DK154419C (en) |
| ES (2) | ES8302733A1 (en) |
| PH (3) | PH18087A (en) |
| ZA (1) | ZA816564B (en) |
Families Citing this family (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4411834A (en) * | 1978-02-09 | 1983-10-25 | Farmitalia Carlo Erba, S.P.A. | Preparation of II-deoxy anthracycline antibiotics |
| IT1210476B (en) * | 1981-05-28 | 1989-09-14 | Erba Farmitalia | ANTHRACYCLINES. |
| CA1187434A (en) * | 1981-08-11 | 1985-05-21 | Akihiro Yoshimoto | Anthracycline antibiotics and their preparation method |
| US4563444A (en) * | 1982-05-26 | 1986-01-07 | Farmitalia Carlo Erba S.P.A. | Anthracycline glycosides, use and compositions containing same |
| FR2551057B1 (en) * | 1983-08-30 | 1986-07-18 | Hoechst Lab | NOVEL AGLYCONES USEFUL FOR THE PREPARATION OF ANTIBIOTICS AND ANTITUMOR OF THE ANTHRACYCLINE SERIES AND METHODS OF PREPARING THE SAME |
| GB8426672D0 (en) * | 1984-10-22 | 1984-11-28 | Erba Farmitalia | Pharmaceutical compositions |
| IT1190399B (en) * | 1985-10-04 | 1988-02-16 | Zambon Spa | PROCESS FOR THE PREPARATION OF OPTICALLY ACTIVE CARBONYL COMPOUNDS |
| JPH0372492A (en) * | 1990-08-04 | 1991-03-27 | Mercian Corp | Anthracycline derivative and its production |
| WO1999058543A1 (en) * | 1998-05-13 | 1999-11-18 | Instytut Farmaceutyczny | New n-alkyloxycarbonyl derivatives of monosaccharides l-acosamine and l-daunosamine |
| EP1165578B1 (en) * | 1999-03-19 | 2012-02-22 | Waldemar Priebe | Methods and compositions for the manufacture of c-3' and c-4' anthracycline antibiotics |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR1527892A (en) * | 1967-03-15 | 1968-06-07 | Rhone Poulenc Sa | New process for preparing the antibiotic 13057 r.p. |
| YU33730B (en) * | 1967-04-18 | 1978-02-28 | Farmaceutici Italia | Process for preparing a novel antibiotic substance and salts thereof |
| US4020270A (en) * | 1974-05-02 | 1977-04-26 | Societa' Farmaceutici Italia S.P.A. | L-lyxohex-1-enopyranose derivative |
| GB1470860A (en) * | 1974-10-29 | 1977-04-21 | Farmaceutici Italia | Anthracycline glycosides |
| GB1500421A (en) * | 1975-01-22 | 1978-02-08 | Farmaceutici Italia | Optically active anthracyclinones |
| GB1527050A (en) * | 1976-06-19 | 1978-10-04 | Farmaceutici Italia | Optically active anthracyclinones |
| NL7900869A (en) * | 1978-02-09 | 1979-08-13 | Erba Farmitalia | ANTHRACYCLINS ANTIBIOTICS. |
| GB2036021B (en) * | 1978-11-21 | 1983-04-13 | Erba Farmitalia | Antitumour antibiotics |
| GB2067552B (en) * | 1980-01-16 | 1984-02-29 | Erba Farmitalia | Anthracyline derivatives |
-
1980
- 1980-09-22 JP JP55130645A patent/JPS5756494A/en active Granted
-
1981
- 1981-09-11 US US06/300,874 patent/US4355026A/en not_active Expired - Fee Related
- 1981-09-17 EP EP81107374A patent/EP0049403B1/en not_active Expired
- 1981-09-17 EP EP83101145A patent/EP0086430B1/en not_active Expired
- 1981-09-17 DE DE8181107374T patent/DE3163896D1/en not_active Expired
- 1981-09-21 AU AU75532/81A patent/AU542707B2/en not_active Ceased
- 1981-09-21 DK DK418581A patent/DK154419C/en not_active IP Right Cessation
- 1981-09-21 ES ES505656A patent/ES8302733A1/en not_active Expired
- 1981-09-21 PH PH26235A patent/PH18087A/en unknown
- 1981-09-21 CA CA000386277A patent/CA1177070A/en not_active Expired
- 1981-09-22 ZA ZA816564A patent/ZA816564B/en unknown
-
1982
- 1982-08-11 ES ES514919A patent/ES8306765A1/en not_active Expired
-
1983
- 1983-04-18 PH PH28790A patent/PH18162A/en unknown
- 1983-10-07 PH PH29674A patent/PH18633A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| EP0086430A1 (en) | 1983-08-24 |
| JPS5756494A (en) | 1982-04-05 |
| EP0049403A3 (en) | 1982-06-02 |
| ES505656A0 (en) | 1982-12-01 |
| PH18162A (en) | 1985-04-03 |
| PH18087A (en) | 1985-03-20 |
| CA1177070A (en) | 1984-10-30 |
| DK154419C (en) | 1989-04-10 |
| PH18633A (en) | 1985-08-23 |
| DK154419B (en) | 1988-11-14 |
| ES514919A0 (en) | 1983-06-01 |
| ZA816564B (en) | 1982-09-29 |
| EP0049403A2 (en) | 1982-04-14 |
| US4355026A (en) | 1982-10-19 |
| EP0049403B1 (en) | 1984-05-30 |
| AU7553281A (en) | 1982-04-01 |
| EP0086430B1 (en) | 1985-11-06 |
| DE3163896D1 (en) | 1984-07-05 |
| DK418581A (en) | 1982-03-23 |
| ES8302733A1 (en) | 1982-12-01 |
| AU542707B2 (en) | 1985-03-07 |
| ES8306765A1 (en) | 1983-06-01 |
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